Aligning Science Across Parkinson's

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Our Collaborators

Thanks to our network of collaborators who help us promote open science.

Browse Research Outputs

Open Access Policy

By supporting an open access policy, we facilitate the rapid and free exchange of scientific ideas, ensuring that the research we fund can be leveraged for future discoveries.

Read the Policy

COLLABORATION

The Aligning Science Across Parkinson’s (ASAP) initiative is devoted to accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing.

Support Collaboration

Fund international multidisciplinary teams to encourage the exchange of ideas, foster innovation, and catalyze new experimental approaches.

Generate Resources

Build infrastructure to support the next generation of Parkinson’s research through genetic analysis efforts, training support, natural history studies, and other research tools.

Share Data

Implement open science policies to ensure that ASAP-funded research, outputs, and tools can be leveraged by the broader community.

Explore the Grantees

Learn about the work of the fourteen awarded teams.

Learn about the work of the fourteen awarded teams.

Learn about the work of the seven awarded teams.

The research discoveries largely centered around 4 categories:

1. Selective Autophagy

Dysfunction of selective autophagic mechanisms have been directly linked to PD. ASAP teams published articles that centered on understanding autophagosome biogenesis, elongation, and downstream mechanisms, with specific insights on mitophagy and lysophagy. 

2. Alpha-Synuclein and Tau Pathology

Protein aggregation has been implicated in the progression of neurodegenerative disorders, such as PD. Focusing specifically on the proteins alpha-synuclein and tau, ASAP teams explored how protein aggregation begins and how it can be hindered or enhanced.

3. LRRK2 Biology

LRRK2 mutations are the most common genetic causes for PD. ASAP teams focused on understanding the LRRK2 interactome and how LRRK2 mutations impact downstream signaling pathways.

4.  Comparative Analysis Between Parkinson’s Disease and Other Diseases

Diseases are often complex and multi-systemic, and as such can have shared pathophysiology. ASAP teams explored PD in the context of other diseases and created tools to better evaluate risk loci.

Guiding Principles

ASAP is guided by the belief that research outcomes will be improved through the following principles:

Collaboration

Given the multifactorial nature of Parkinson’s disease, charting a new path will require multidisciplinary cooperation from investigators with and without a previous record of PD research.

Creativity

Philanthropic capital has the most impact in areas that are deemed unpopular, high-risk, or out-of-scope for government funding, requiring creative and thoughtful consideration of research.

Flexibility

As roadmap goals are implemented, we will be responsive to the evolving nature of research and adjust focus as deemed appropriate.

Transparency

To accelerate research, we’ll support the free flow of data and resources within our collaborative network and make findings available to the broader community.

Be a part of a global initiative to influence the culture of the way we do science.

Since the first identification of a causal genetic mutation in Parkinson’s disease (PD), genetic discoveries have expanded our understanding of PD heredity and broadened insights into spontaneous disease. The focus across these teams will be to unravel the biology underlying these genetic mutations.

Be a Part of Our Mission

We’re enabling science to go further, faster, and at a greater scale. Follow @ASAP_Research across our social media channels and join our mailing list for exciting updates as our work matures. 

Sign up for updates here.

CRN_Logo_White_RGB
results.
CRN_Logo_White_RGB

The ASAP Collaborative Research Network is an international, multidisciplinary, and multi-institutional network of 35 teams working to address research and knowledge gaps in the development and progression of PD.

The CRN was designed to create an environment that facilitates the rapid and free exchange of scientific ideas that would spark new discoveries for PD.

“Parkinson’s Disease presents a challenging scientific problem as well as a major unmet medical need. The ASAP Initiative offers an opportunity for major innovative impact on both fronts in this important area.”

35 Teams Funded

$290M+ in Grant Funding Awarded Over Four Years

163 Investigators Total as Team Leaders

Uncovering the roots of Parkinson's disease, together

A global basic research initiative

Announcing the Newest Members of the CRN

The ASAP Collaborative Research Network (CRN) continues to expand, attracting new investigators across multiple disciplines, institutions, career stages, and geographies. Working together, the CRN addresses gaps in the development and progression of Parkinson’s disease. This year, we welcome 14 new research teams who will focus their work on circuitry and brain-body interactions.

Scientific Themes

Biology of PD-Associated Genetics

The effect of genetic alterations on disease biology

Neuro-Immune Interactions

The molecular and cellular contributions of the neuro-immune system

Circuitry and Brain-Body Interactions

The underlying neuronal circuit dynamics and interface with the periphery

Progression: A Cross-Cutting Theme

The role of heredity, neuro-immune factors, and circuit-level alterations on disease progression

What causes it?

The cause is unknown; however, there are a number of known risk factors. Men are 50 percent more likely than women to develop Parkinson’s disease; exposure to pesticides and other toxins increases risk. Head trauma and depression are also thought to increase a person’s chances of developing Parkinson’s disease. A number of recently discovered genetic risk variants are reported to increase a person’s risk as well – these may prove scientifically useful in identifying the underlying mechanisms of Parkinson’s disease.

How is it treated today?

Although there are some therapies that help with the symptoms of Parkinson’s disease, none can address the underlying cause of the disease. Levodopa is a drug that replaces dopamine, the main chemical produced by the neurons that Parkinson’s disease attacks. However, its effect tends to wear off after four to seven years and can cause unwanted side effects. Other drug treatments try to mimic the action of dopamine, protect it from breakdown or preserve motor function through other molecular pathways. And for some people with Parkinson’s disease, surgically implanted electrodes can relieve symptoms.

Can we develop more effective treatments?

Because we currently have little understanding of how Parkinson’s disease starts and progresses, the challenge of developing a disease-modifying drug is formidable. Researchers and clinicians lack a reliable diagnostic or biomarkers that can be used to determine whether a candidate drug affects disease progression at a cellular level.

ASAP is a coordinated research initiative to advance targeted basic research for Parkinson’s disease. Led by Nobel Laureate Dr. Randy Schekman and Dr. Ekemini Riley, ASAP is managed by the Coalition for Aligning Science and is working with The Michael J. Fox Foundation to implement its programs. The initiative was incubated at the Milken Institute Center for Strategic Philanthropy with support from the Sergey Brin Family Foundation.

Aligning Science Across Parkinson’s (ASAP) is fostering collaboration and resources to better understand the underlying causes of Parkinson’s disease. With scale, transparency, and open access data sharing, we believe we can accelerate the pace of discovery, and inform the path to a cure.

Latest News

With Thanks to Our Collaborators

Meet ASAP’s 2020 Grantees

Meet the new members of ASAP’s Collaborative Research Network. Multidisciplinary investigators in 21 teams from 60 institutions across 11 countries, seek to accelerate targeted basic research and move us toward more meaningful advancements for Parkinson’s Disease. Get to know these talented scientists, their projects and how their outcomes will contribute to the field of PD.

GP2 Launches Training Platform

GP2’s new online learning platform makes development opportunities accessible and enables learners from around the world to explore courses on topics related to Parkinson’s disease genetics and a range of related areas. It is easy to register and available to everyone interested.

OUR VISION:

Collaborative and transparent research processes and environments that deliver faster and better outcomes for Parkinson’s disease.

OUR MISSION:

Accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing.

Increasing Hispanic Representation in Parkinson's and Genomic Research

Human genetics and epidemiological studies are valuable tools for understanding Parkinson’s disease, but research has found that known genetic factors identified in European populations play an insignificant role in the development of PD in Latinos. LARGE-PD, an ASAP partner and multicenter collaboration across Latin America, is working to increase Latino and Hispanic representation in this field of research. Read GP2’s latest blog post. 

In 2021 we announced the second round—and the third group—of the ASAP CRN grantees focused on circuitry and brain-body interactions, to complete our network.
We also kicked off the production phase for teams undertaking PD functional genomics and neuro-immune reactions and marked the beginning of the fully operational phase for our network.
All grantees have access to the ASAP Hub where they interact and work in partnership with others in the network. 

Current Scientific Advisory Board

Paola Arlotta, PhD
Biography

Paola Arlotta, PhD

Harvard University | USA
David Ginsburg, MD
Biography

David Ginsburg, MD

University of Michigan Medical School | USA
William J. Marks, Jr., MD, MS-HCM
Biography
Hollis Cline, PhD
Biography

Hollis Cline, PhD

Scripps Research Institute | USA
Bernardo Sabatini, MD, PhD
Biography

Bernardo Sabatini, MD, PhD

Harvard Medical School | USA
Carla Shatz, PhD
Biography

Carla Shatz, PhD

Stanford University | USA

We’re enabling science to go further, faster, and at a greater scale. Join us to receive updates.

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PD Functional Genomics | 2020

Mapping the LRRK2 Signaling Pathway and Its Interplay with Other Parkinson’s Disease Components

Study Rationale: Genetic mutations that lead to the activation of the enzyme LRRK2 are a major cause of inherited Parkinson’s disease. Team Alessi aims to combine the complementary expertise of its four research laboratories to perform fundamental, state-of-the-art experimentation to better comprehend the biology that is controlled by LRRK2. Team Alessi’s goal is to gain a much better understanding of LRRK2-driven Parkinson’s disease, hopefully providing a foundation for the development of future therapies.

Hypothesis: LRRK2 targets and modifies a set of enzymes known as Rab GTPases, triggering new biological events by creating new protein: protein interactions. Team Alessi aims to decipher what controls the activity of LRRK2 and to explore, in precise molecular detail, how this enzyme affects three major cellular structures (cilia, lysosomes, and mitochondria) implicated in Parkinson’s disease.

Study Design: Team Alessi showed that mutant LRRK2 triggers a series of molecular changes that cause new sets of proteins to interact. Team Alessi’s goal is to use a combination of state-of-the-art approaches to understand the consequences of these new interactions on the biology of three important subcellular compartments: primary cilia, lysosomes, and mitochondria.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Alessi’s findings will provide novel, fundamental information of relevance to understanding the origin and progression of Parkinson’s that they hope will lead to new ideas to better diagnose, treat, and even prevent this malady in the future.

Leadership
Dario Alessi, PhD
Coordinating Lead PI

Dario Alessi, PhD

University of Dundee
Miratul Muqit, MD, PhD
Co-Investigator

Miratul Muqit, MD, PhD

University of Dundee
Monther Abu-Remaileh, PhD
Co-Investigator

Monther Abu-Remaileh, PhD

Stanford University
Suzanne Pfeffer, PhD
Co-Investigator

Suzanne Pfeffer, PhD

Stanford University
Francesca Tonelli
Project Manager

Francesca Tonelli

University of Dundee

Project Outcomes

The project will provide fundamental information regarding how mutations in LRRK2 cause Parkinson's disease. View Team Outcomes. Learn more about the team. Meet the Investigators.

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PD Functional Genomics | 2020

Impaired Integration of Organelle Function in Parkinson’s Disease

Study Rationale: Geneticists have made great progress in identifying gene mutations that either cause Parkinson’s or increase disease risk. The critical next step is to determine how some of these mutations perturb the function of brain cells involved in Parkinson’s disease. By advancing knowledge of these processes, Team De Camilli’s research will help to identify new opportunities for reversing the vulnerabilities that cause the disease.

Hypothesis: Team De Camilli hypothesizes that the functions of multiple Parkinson’s disease genes converge on common biochemical pathways involving endocytic organelles and/or mitochondria within vulnerable cell types.

Study Design: Team De Camilli will use a comprehensive cell biology tool kit including cutting-edge biochemistry, structural biology, microscopy at different scales, and genome editing tools to elucidate the function of selected Parkinson’s disease genes and the effects produced by their dysfunction both in cellular models in vitro and in mouse and rat models. By defining the molecular and cellular networks in which the products of these genes operate, Team De Camilli hopes to identify strategies for reversing the cellular vulnerabilities that cause Parkinson’s disease or increase disease risk.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Similar to assembling the pieces of a puzzle, the project has the potential to reveal interconnections between the functions of distinct Parkinson’s disease genes, thus helping to build an understanding of Parkinson’s disease cell biology. This is a critical step towards the development of therapeutic strategies to make neurons resistant to the dysfunctions that cause Parkinson’s disease.

Leadership
Pietro De Camilli, MD
Coordinating Lead PI

Pietro De Camilli, MD

Yale University
Kallol Gupta, PhD
Co-Investigator

Kallol Gupta, PhD

Yale University
Karin Reinisch, PhD
Co-Investigator

Karin Reinisch, PhD

Yale University
Shawn Ferguson, PhD
Co-Investigator

Shawn Ferguson, PhD

Yale University
Timothy Ryan, PhD
Co-Investigator

Timothy Ryan, PhD

Weill Cornell Medicine
Berrak Ugur, PhD
Project Manager

Berrak Ugur, PhD

Yale University

Project Outcomes

The project hopes to reveal interconnections between the functions of distinct Parkinson’s disease genes, thus helping to identify cellular processes whose dysfunction confers Parkinson’s disease vulnerability and which may be targeted for therapeutic intervention. View Team Outcomes.

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PD Functional Genomics | 2020

Dissecting the Mechanisms Underlying Disease Progression

Study Rationale: The progression of Parkinson’s disease is very variable, with some individuals having a rapid course and others having a longer and more benign course. Team Hardy believes that by understanding the genetics and the mechanistic basis of this variability, they will be able to design therapies to slow Parkinson’s progression. Team Hardy has already found that GBA mutations lead to a rapid disease course and that LRRK2, linked to familial forms of Parkinson’s, influences the course of parkinsonism in another disease: progressive supranuclear palsy. They will test whether modulating these enzymes influences the course of pathology spread in a pre-clinical model of progression as a validation of this approach to disease treatment.

Hypothesis: Team Hardy wants to find and understand the genes that are involved in Parkinson’s progression and test whether modulating them pharmacologically influences disease progression.

Study Design: Through genetic analysis, Team Hardy will find genes that influence the progression of parkinsonism, and then assess the mechanisms by which they affect disease development. They have already found that GBA and LRRK2 influence clinical rates of decline so Team Hardy will test, in a mouse model of pathology progression, whether inhibiting these enzymes influences pathology spread and thereby develop a relevant platform to test drugs for slowing disease progression.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This research will impact Parkinson’s care in three ways. First, by understanding the genetics of rate of decline, these data can be factored into clinical trial design and possibly more generally into clinical practice. Second, the identification of pathways involved in disease progression is likely to reveal further drug targets. And thirdly, the testing of GBA and LRRK2 inhibitors in a mouse model of disease progression will test this as a valid approach to treatment development.

Leadership
John Hardy, PhD
COORDINATING LEAD PI

John Hardy, PhD

University College London
Frances Platt, PhD
Co-Investigator

Frances Platt, PhD

University of Oxford
Maria Grazia Spillantini, PhD
Co-investigator

Maria Grazia Spillantini, PhD

University of Cambridge
Mina Ryten, MD, PhD
Co-Investigator

Mina Ryten, MD, PhD

University College London
Zane Jaunmuktane, MD
Co-Investigator

Zane Jaunmuktane, MD

University College London
Oke Avwenagha, PhD
Project Manager

Oke Avwenagha, PhD

University College London

Project Outcomes

Team Hardy will dissect the genetic and gene expression variability underlying differences in the rate of decline inherent in PD and move towards therapies which slow this decline. View Team Outcomes.

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PD Functional Genomics | 2020

Mechanisms Overwhelming Protein and Organelle Quality Control in Parkinson’s Disease

Study Rationale: Abnormal protein aggregation and prion-like aggregate spreading are hallmarks of the degenerative cascades of sporadic and familial Parkinson’s disease (PD) and can damage cells, including neurons. Multiple mechanisms of aggregate toxicity have been implicated in cellular PD pathology, and PD risk alleles may have the potential to illuminate additional underlying biological mechanisms.

Hypothesis: Parkinson’s disease, at the molecular level, results from the failure of cellular quality control (QC) mechanisms, and finding ways to maintain (or augment) QC capacity will provide new therapeutic strategies for PD and possibly other neurodegenerative disorders.

Study Design: Using powerful molecular visualization and discovery tools in disease-relevant cells, Team Harper will elucidate how individual types of protein aggregates linked with PD strains (including patient-derived aggregates) alter cellular pathways, including effects on cell survival and function. Team Harper will also use genetic approaches to understand what cellular proteins promote the processing of PD-related aggregates.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Harper’s expectation is that this work will identify those critical cellular functions that are disrupted by protein aggregates and will help define how mutations alter the underlying mechanisms of dysfunctional proteostasis.

Leadership
J. Wade Harper, PhD
COORDINATING LEAD PI

J. Wade Harper, PhD

Harvard University
Ruben Fernandez-Busnadiego, PhD
Co-Investigator

Ruben Fernandez-Busnadiego, PhD

Universität Göttingen
Judith Frydman, PhD
CO-INVESTIGATOR

Judith Frydman, PhD

Stanford University
Franz-Ulrich Hartl, MD
Co-Investigator

Franz-Ulrich Hartl, MD

Max Planck Institute of Biochemistry
Brenda Schulman, PhD
Co-Investigator

Brenda Schulman, PhD

Max Planck Institute of Biochemistry
Felix Kraus, PhD
Project Manager

Felix Kraus, PhD

Harvard University

Project Outcomes

Through biochemical reconstitution, in situ structural analysis, and genetic perturbations, this project will directly visualize pathogenic mechanisms in cells and in reconstituted systems at nanometer and subnanometer resolution, providing an unprecedented understanding of how a-synuclein strains and other PD mutants promote cellular dysfunction. View Team Outcomes.

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PD Functional Genomics | 2020

Mechanisms of Mitochondrial Damage Control by PINK1 and Parkin

Study Rationale: Mitochondria are tiny power-generating stations within all cells, including neurons. They are vital energy producers, but when things go wrong, they can spew toxic materials and sicken or kill neurons. The clean-up crew for mitochondria gone wrong is called “mitophagy” (as in “eating mitochondria”) and is directed by two proteins called PINK1 and parkin. Studies of Parkinson’s disease have taught researchers that PINK1, parkin and mitophagy are very important in preventing disease.

Hypothesis: The purpose of this project is to figure out how PINK1, parkin and mitophagy work together to prevent disease. Once Team Hurley knows how they work together, they hope to figure out how to make them work faster and better, so that they can prevent Parkinson’s disease from ever starting.

Study Design: Team Hurley thinks of PINK1, parkin and the proteins of mitophagy as nanomachines. They call their type of research “mechanistic” because it seeks to understand how these machines work. Team Hurley relies heavily on the most powerful light and electron microscopes available, and they also use genome engineering of stem cells to make versions of neurons that are easier to study.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Hurley’s dream is to understand PINK1, parkin, and mitophagy so well that they can build a computerized description of the pathway that will be able to predict which drugs and treatments will help the mitochondrial clean-up crew enough to prevent or cure disease.

Leadership
James Hurley, PhD
Coordinating Lead PI

James Hurley, PhD

University of California at Berkeley
Erika Holzbaur, PhD
CO-INVESTIGATOR

Erika Holzbaur, PhD

University of Pennsylvania
Eunyong Park, PhD
CO-INVESTIGATOR

Eunyong Park, PhD

University of California at Berkeley
Michael Lazarou, PhD
CO-INVESTIGATOR

Michael Lazarou, PhD

Monash University
Sascha Marten, PhD
CO-INVESTIGATOR

Sascha Marten, PhD

Max Perutz Labs at the University of Vienna
Dorotea Fracchiolla, PhD
Project Manager

Dorotea Fracchiolla, PhD

Max Planck Institute of Biophysics

Project Outcomes

If successful, the project will provide a therapeutically actionable basis for where and how mitophagy can best be activated to promote the health and longevity of the dopaminergic neurons affected in Parkinson's Disease. View Team Outcomes.

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PD Functional Genomics | 2020

In Vivo Approach to Elucidate the Pathobiology of Parkinson’s-associated Genes Using Human Diseased Neurons

Study Rationale: Several genes are known to be associated with Parkinson’s disease, although how they impact the disease process is not fully understood. Team Kirik will use stem cells from patients in whom the genetic cause is known and perform mechanistic studies to elucidate the interactions between three key genes and how they impact the function of cells in the brain.

Hypothesis: This project will provide new insights into the role specific gene mutations play in the development of disease features in cell types known to be affected in Parkinson’s disease.

Study Design: Stem cells generated from patients with neurological disease, including Parkinson’s disease, provide a tool for researchers to study and understand mechanisms underlying the disease. One limitation of this approach is that the cells are maintained in culture dishes in the laboratory in an artificial environment that does not closely model that of the disease. This project proposes a unique approach involving the transplantation of the human cells into mice in order to study them in the living brain and thus reveal new insights into disease mechanisms.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Researchers’ ability to design better treatments for Parkinson’s is directly related to the level of understanding on the basic biological processes governing the initiation of the disease process and how the disease progresses from that point onward. This information is critical in efforts to intervene with the disease process.

Leadership
Deniz Kirik, MD, PhD
COORDINATING LEAD PI

Deniz Kirik, MD, PhD

University of Sydney
Clare Parish, PhD
CO-INVESTIGATOR

Clare Parish, PhD

University of Melbourne
Jennifer Johnston, PhD
CO-INVESTIGATOR

Jennifer Johnston, PhD

NysnoBio, LLC
Lachlan Thompson, PhD
CO-INVESTIGATOR

Lachlan Thompson, PhD

University of Sydney
Courtney Wright, PhD
Project Manager

Courtney Wright, PhD

University of Sydney
Glenda Halliday, PhD
Co-Investigator

Glenda Halliday, PhD

University of Sydney

Project Outcomes

This project will use patient-derived cells from genetic forms of PD, studied in the environment of the living brain, as a unique paradigm to reveal cellular components of PD pathobiology. View Team Outcomes.

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PD Functional Genomics | 2020

Senescence in Parkinson’s Disease and Related Disorders

Study Rationale: While aging is the greatest risk factor for the development of Parkinson’s disease (PD), how aging promotes PD is not fully understood. Examining the role of cellular senescence (deterioration of function), a major driver of aging, in PD represents a completely novel approach to understanding disease pathophysiology and may lead to new therapeutic approaches.

Hypothesis: Senescence and PD-linked gene mutations have reciprocal pathological interactions where (i) senescence causes PD-relevant neuropathology; (ii) PD-linked mutant genes (alpha-synuclein, LRRK2, Vps35) cause premature senescence; and (iii) senescence participates in neuropathology caused by PD-linked genes.

Study Design: First, Team Lee will use novel mouse models of premature senescence to test whether premature senescence in specific cell types causes PD-like neuropathology. Second, they will combine mouse models of senescence and familial PD to test whether senescence participates in neuropathology caused by mutant PD-linked genes. Specifically, Team Lee will determine if pathology in a PD mouse model causes premature senescence and whether removing senescent cells from brain can prevent PD pathology. Finally, Team Lee will perform gene expression analysis of PD brains and mouse brains, at a single-cell level, to gain high-resolution insights about cellular processes that link aging and PD pathology.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Lee’s results will support the use of senolytics (drugs that selectively kill senescent cells and are currently in Phase II clinical trials) as novel disease-modifying therapies for PD. In addition, Team Lee’s studies may identify new biomarkers of senescence in PD.

Leadership
Michael Lee, PhD
COORDINATING LEAD PI

Michael Lee, PhD

University of Minnesota
Darren Moore, PhD
CO-INVESTIGATOR

Darren Moore, PhD

Van Andel Institute
Laura Niedernhofer, MD, PhD
CO-INVESTIGATOR

Laura Niedernhofer, MD, PhD

University of Minnesota
Jane Balster, MA
Project Manager

Jane Balster, MA

University of Minnesota
Michael Henderson, PhD
Co-Investigator

Michael Henderson, PhD

Van Andel Institute

Project Outcomes

This project will determine if cellular senescence is a pathogenic component of Parkinson’s disease and test if drugs targeting senescent cells can be used as a disease-modifying therapy for PD. View Team Outcomes.

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PD Functional Genomics | 2020

Cellular Mechanism of LRRK2 in Health and Disease

Study Rationale: Leucine Rich Repeat Kinase 2 (LRRK2) is the most commonly mutated gene in inherited forms of Parkinson’s disease (PD). The LRRK2 gene codes for a protein kinase, an enzyme that adds chemical groups to other proteins to change their activity inside cells. However, researchers currently do not understand how LRRK2 normally works and why its malfunction causes PD. Importantly, LRRK2 has also been shown to function abnormally in PD patients that have the sporadic form of the disease, making LRRK2 one of the most promising targets for drug development.

Hypothesis: Team Reck-Peterson recently discovered that chains of the LRRK2 protein can wrap around cellular highways called “microtubules”. Their work suggests that LRRK2 blocks the cellular machines that move on these highways. Team Reck-Peterson will explore the idea that mutations in LRRK2 cause PD by acting as roadblocks that change the normal transport of chemical information inside cells. They will test additional ideas that arise from the experiments they perform.

Study Design: The collaborative team includes experts in cryo-electron microscopy (Cryo-EM), cryo-electron tomography (Cryo-ET), small molecule synthesis, proteomics, and single-molecule and live-cell imaging. The team will use their expertise to solve structures of multiple conformations and variants of LRRK2 to manipulate these different pools of LRRK2 and understand their cellular functions. Team Reck-Peterson will determine how LRRK2 binds to microtubules and affects microtubule-based motors. They will also identify the protein interaction landscape of LRRK2 and test emergent cellular hypotheses resulting from this work, including whether LRRK2 regulates the transport of chemical information on microtubules.

Impact on Diagnosis/Treatment of Parkinson’s Disease: A major barrier to developing LRRK2-based PD therapy has been the lack of a blueprint of LRRK2’s three-dimensional shape, alone or interacting with other molecules it comes into contact with inside human cells. Team Reck-Peterson expects that the work will reveal what LRRK2 looks like, what it does in cells, and why its malfunction causes PD. The work will be critical for the design of drugs targeting LRRK2.

Leadership
Samara Reck-Peterson, PhD
COORDINATING LEAD PI

Samara Reck-Peterson, PhD

University of California at San Diego
Andres Leschziner, PhD
CO-INVESTIGATOR

Andres Leschziner, PhD

University of California at San Diego
Elizabeth Villa, PhD
CO-INVESTIGATOR

Elizabeth Villa, PhD

University of California at San Diego
Florian Stengel, PhD
CO-INVESTIGATOR

Florian Stengel, PhD

University of Konstanz
Stefan Knapp, PhD
CO-INVESTIGATOR

Stefan Knapp, PhD

Goethe-Universität
Robert Fagiewicz, PhD
Project Manager

Robert Fagiewicz, PhD

University of California at San Diego

Project Outcomes

Team Reck-Peterson's work on LRRK2 will provide a comprehensive understanding of the structure and conformation-dependent association with cellular partners of this key target for the development of Parkinson’s disease therapeutics. View Team Outcomes.

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PD Functional Genomics | 2020

Dissecting Genetic Interactions of Parkinson’s Disease-associated Risk Loci

Study Rationale: Parkinson’s disease can have multiple complex causes, including genetic and environmental, that are not fully understood. Team Rio will combine modern genetic and human stem cell-based approaches to determine how heritable genetic changes affect Parkinson’s disease predisposition. By identifying how even small genetic changes can compound the risk of developing Parkinson’s disease, Team Rio hopes to identify new ways to detect and treat the disease in the future.

Hypothesis: Team Rio hypothesizes that combining complex human cell culture models such as 3-dimensional brain organoids with sophisticated genome-scale functional analysis will allow the team to elucidate how diverse genetic factors interact and contribute to the risk of developing Parkinson’s disease, thereby informing the development of early detection diagnostics and advanced treatment options.

Study Design: Team Rio will genetically engineer human embryonic stem cells to model the genetic alterations known to increase risk for Parkinson’s disease and turn those cells into disease-relevant cell types such as dopamine neurons. By profiling the gene expression changes caused by these known Parkinson’s disease risk variants, the team will decipher the key molecular signatures that contribute to Parkinson’s disease. Once identified, the team will confirm these genetic signatures in patient samples and validate their effects in animal models.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Elucidating how Parkinson’s disease genetic risk variants affect cell biology has promise to identify disease-specific biomarkers and novel treatment options.

Leadership
Donald Rio, PhD
COORDINATING LEAD PI

Donald Rio, PhD

University of California at Berkeley
Dirk Hockemeyer, PhD
CO-INVESTIGATOR

Dirk Hockemeyer, PhD

University of California at Berkeley
Frank Soldner, MD
CO-INVESTIGATOR

Frank Soldner, MD

Albert Einstein College of Medicine
Helen Bateup, PhD
CO-INVESTIGATOR

Helen Bateup, PhD

University of California at Berkeley
Ezgi Booth, PhD
Project Manager

Ezgi Booth, PhD

University of California at Berkeley

Project Outcomes

This project uses state-of-the-art functional genomics approaches to identify gene expression and RNA splicing signatures that may lead to the development of novel pharmacological interventions for Parkinson’s disease or biomarkers for early diagnosis and disease progression. View Team Outcomes.

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PD Functional Genomics | 2020

Parkinson5D: Deconstructing Proximal Disease Mechanisms Across Cells, Space, and Progression

Study Rationale: Genome-wide association studies (GWAS) have unequivocally linked thousands of noncoding variants in ninety independent GWAS signals to susceptibility for common, genetically complex Parkinson’s disease (PD) that affects more than 7 million people around the world. Why have these breakthroughs not uncovered the mechanism(s) of PD? Researchers do not know how disease-associated variants cause neurodegeneration and why they impair some brain cells but not others. Team Scherzer’s research will tackle the critical task of clarifying the precise mechanisms through which this wealth of genetic variation regulates onset and progression of PD.

Hypothesis: Team Scherzer hypothesizes that most GWAS variants function through cell-, space-, and stage-dependent gene-regulatory mechanisms.

Study Design: Here Team Scherzer will develop a molecular atlas of PD that reveals how GWAS/familial genetics control proximal disease mechanisms in five dimensions: brain cells (1D), brain space (3D), and disease stage (1D). The team will reveal how genetic variants modulate mechanisms in specific brain cells in specific topographic locations of midbrain and cortex during the progression of neuropathology from healthy brains to prodromal to symptomatic disease. Massively parallel analysis of hundreds of thousands of single human brain cells with genetic transcriptomics, high-resolution spatial transcriptomics, and fine-mapping of causal alleles with allelic imbalance in human brains will be combined with the prodigious power of cell- and stage-specific mechanistic analyses in brain of Drosophila avatars and in vitro in human pluripotent stem cells.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Scherzer’s collaborative and integrative project will translate the complex human genetics of PD into a dynamic, five-dimensional view of proximal cellular mechanisms. It will begin to reveal how single nucleotide variation in a person’s universal DNA code regulates gene activity (without changing protein sequence) in situ in billions of physiologically specialized neurons and glia cells, and determines, how, when, which, and where brain cells are destined to malfunction.

Leadership
Clemens Scherzer, MD
COORDINATING LEAD PI

Clemens Scherzer, MD

Brigham and Women's Hospital at the Harvard Medical School
Joshua Levin, PhD
CO-INVESTIGATOR

Joshua Levin, PhD

Broad Institute
Mel B. Feany, MD, PhD
CO-INVESTIGATOR

Mel B. Feany, MD, PhD

Brigham and Women's Hospital at the Harvard Medical School
Su-Chun Zhang, MD, PhD
CO-INVESTIGATOR

Su-Chun Zhang, MD, PhD

University of Wisconsin-Madison
Xianjun Dong, PhD
CO-INVESTIGATOR

Xianjun Dong, PhD

Brigham and Women's Hospital at the Harvard Medical School
Beatrice Weykopf, PhD
Project Manager

Beatrice Weykopf, PhD

Yale University

Project Outcomes

Parkinson5D will translate the complex human genetics of Parkinson’s disease into a dynamic, spatiotemporal understanding of proximal mechanisms in specific brain cells --- in situ in patients’ brains, in vivo in Drosophila, and in vitro using human pluripotent stem cell genetics. It will begin to reveal how single nucleotide variation in a person’s universal DNA code regulates gene activity in situ in billions of physiologically specialized neurons and glia cells, and determines, how, when, which, and where brain cells are destined to malfunction. View Team Outcomes.

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PD Functional Genomics | 2020

Defining the Cellular and Molecular Determinants of Variable Genetic Penetrance in Parkinson’s Disease

Study Rationale: Why do some people develop Parkinson’s disease (PD) while others do not? Although many genetic risk factors have been identified, researchers still cannot confidently answer this question, or explain how certain cells in the brain go from being healthy early in life to diseased in old age. Clearly, numerous complex factors are involved, and a systematic investigation of the key cellular and molecular players is necessary to understand and effectively treat this disease.

Hypothesis: Team Studer hypothesizes that single genetic factors are insufficient to cause PD — rather, that it is triggered by a combination of genetics, age-related factors, and their effects in different brain cells.

Study Design: Here, Team Studer proposes to dissect the genetic, age-related, and cell-type-specific factors that lead to PD using a collection of genetically diverse stem cells derived from patients. Using advanced methods pioneered by the team, they will convert these stem cells into the different types of brain cells implicated in PD — neurons, microglia, and astrocytes — allowing the team to investigate how genetic risk factors, the aging process, and these different cell types interact to trigger disease. Team Studer will assess how various combinations of these factors disrupt the function of brain cells using detailed molecular studies, microscopy, genetic manipulations, and biochemical measurements — building a computational network model of the factors that cause PD.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This richer, fully human cell model of PD will provide an entirely new level of understanding of how the interplay between genetics, different brain cells, and aging shapes individual disease risk, enabling early diagnosis, prediction of therapeutic targets that could halt or reverse the disease, and stratification of patients into therapeutically meaningful subgroups.

Leadership
Lorenz Studer, MD
COORDINATING LEAD PI

Lorenz Studer, MD

Memorial Sloan Kettering Cancer Center
Gist Croft, PhD
CO-INVESTIGATOR

Gist Croft, PhD

New York Stem Cell Foundation
Joseph Powell, PhD
CO-INVESTIGATOR

Joseph Powell, PhD

Garvan Institute for Medical Research
Vikram Khurana, MD, PhD
CO-INVESTIGATOR

Vikram Khurana, MD, PhD

Brigham and Women's Hospital at the Harvard Medical School
Johannes Jungverdorben, PhD
Project Manager

Johannes Jungverdorben, PhD

Memorial Sloan Kettering Cancer Center

Project Outcomes

The project will not only help address the question of variable penetrance — why some individuals with genetic risk factors develop Parkinson’s disease while others do not — but may also lead to improved tools for early diagnosis, prediction of effective therapeutic targets, and stratification of patients into therapeutically meaningful subgroups. View Team Outcomes.

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PD Functional Genomics | 2020

IMPACT-PD – Implications of Polyamine and Glucosylceramide Transport in Parkinson’s Disease

Study Rationale: Mutations in the genes ATP13A2 (PARK9) and ATP10B trigger Parkinson’s disease (PD) and cause dysfunction of lysosomes, the recycling compartments of the cell. Team Vangheluwe explained these defects by impaired transport of polyamines and glucosylceramide out of the lysosome, respectively. Polyamines are cell protective agents, whereas the levels of the lipid glucosylceramide are controlled by GBA1, the major genetic risk factor of PD. However, there is a clear knowledge gap regarding the biology of polyamine and glucosylceramide transport systems in neurons and their supporting cells of the brain, and how an impaired polyamine and glucosylceramide distribution in these cells leads to neurodegeneration.

Hypothesis: Team Vangheluwe hypothesizes that an impaired polyamine and glucosylceramide transport activity causes toxic accumulation of these substances in lysosomes and leads to a shortage elsewhere in the cell. Together, this may cause lysosomal and mitochondrial dysfunction, and lead to α-synuclein toxicity, three major hallmarks of PD.

Study Design: First, Team Vangheluwe will investigate the molecular architecture of polyamine and glucosylceramide transporters and identify mechanisms to modulate their activity. Second, the team will examine how these transporters influence the intracellular distribution of polyamine and glucosylceramide, and how this affects the cross-talk between lysosomes and mitochondria. Third, they will investigate how dysfunctional polyamine and glucosylceramide transporters affect other PD pathways, such as mitophagy, GBA1 and alpha-synuclein aggregation, and whether the modulation of these transporters can be validated as therapeutic approach for PD. Finally, Team Vangheluwe will collect evidence for disturbed polyamine and glucosylceramide transport in PD patients.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Vangheluwe will validate the neuroprotective effect of polyamine and glucosylceramide transporters and investigate their potential to reverse α-synuclein and GBA1 pathology. This may offer new therapeutic strategies that correct aberrant lysosomal and mitochondrial dysfunction in Parkinson’s disease. The team will analyze whether alterations in the polyamine and glucosylceramide levels together may be considered as biomarkers for PD.

Leadership
Peter Vangheluwe, PhD
COORDINATING LEAD PI

Peter Vangheluwe, PhD

KU Leuven
Ellen Sidransky, MD
CO-INVESTIGATOR

Ellen Sidransky, MD

National Human Genome Research Institute
Joel Blanchard, PhD
Co-Investigator

Joel Blanchard, PhD

Icahn School of Medicine at Mount Sinai
Joseph Lyons, PhD
CO-INVESTIGATOR

Joseph Lyons, PhD

University of Aarhus
Veerle Baekelandt, PhD
CO-INVESTIGATOR

Veerle Baekelandt, PhD

KU Leuven
Veronique Daniëls, PhD
Project Manager

Veronique Daniëls, PhD

KU Leuven

Project Outcomes

By dissecting the neuroprotective effect of lysosomal polyamine and glucosylceramide transporters at the molecular level, Team Vangheluwe will establish new pathways implicated in Parkinson’s disease that may serve as novel therapeutic targets to restore lysosomal dysfunction in Parkinson’s disease. View Team Outcomes.

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PD Functional Genomics | 2020

Understanding Inherited and Acquired Genetic Variation in Parkinson’s Disease through Single-Cell Multi-omics Analyses: A Unique Data Resource

Study Rationale: Parkinson’s disease (PD) is a disorder that not only affects the function of the brain, but also of the gut, which are both complex tissues composed of functionally diverse types of cells that need to cooperate for organ function. Around 90 regions of the DNA that we inherit from our parents, show differences between people with and without PD. Furthermore, as we develop and age, new, non-inherited DNA mutations may also be acquired in part of our body cells. How such inherited and newly acquired DNA variants function in increasing the risk of developing PD remains however largely unknown.

Hypothesis: Team Voet hypothesizes that these DNA variants can increase or decrease the activity of key (un)known genes in particular types of cells of the brain and the gut, which in turn increases the risk of developing PD.

Study Design: Team Voet will use the expertise of their consortium in analyzing single cells to study the brain and gut from individuals who lived with and without PD. Specifically, gene expression profiling of over 4,500,000 single cells will allow the team to discover the genes of which the expression is altered by the DNA variants, and importantly, also in which type of brain and/or gut cells the expression of the gene is disturbed. Team Voet will next analyze how these DNA variants change the functioning of these specific cell types, by using their existing models of the fruitfly, and of cultured human nerve and immune gut cells.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This study will provide crucial mechanistic insights into how faults in our DNA change the functioning of specific cells in our brains and guts, and thus cause a predisposition to PD.

Leadership
Thierry Voet, PhD
COORDINATING LEAD PI

Thierry Voet, PhD

KU Leuven
Bernard Thienpont, MD, PhD
CO-INVESTIGATOR

Bernard Thienpont, MD, PhD

KU Leuven
Christos Proukakis, PhD
CO-INVESTIGATOR

Christos Proukakis, PhD

University College London
Guy Boeckxstaens, MD, PhD
CO-INVESTIGATOR

Guy Boeckxstaens, MD, PhD

KU Leuven
Stein Aerts, PhD
CO-INVESTIGATOR

Stein Aerts, PhD

KU Leuven
Sara Salama, PhD
Project Manager

Sara Salama, PhD

KU Leuven

Project Outcomes

By disclosing the Parkinson's disease (PD)-relevant genes and cell (sub)types in the brain and gut, and the molecular mechanisms of their gene expression (dys)regulation in the normal condition, with aging and in PD, Team Voet will advance their understanding of the etiopathogenesis of the disease and pave the path for devising new treatment modalities. View Team Outcomes.

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PD Functional Genomics | 2020

Mapping the PD Brain: Oligomer-driven Functional Genomics

Study Rationale: To determine the molecular and cellular process that lead to PD, a powerful approach is to single out and study the cells where the disease originates. To achieve this goal, Team Wood uses alpha-synuclein oligomers as a cellular biomarker to identify the right cells. The team will then apply state-of-the-art genomic and genetic analyses to identify genes and proteins that form the disease pathways. Team Wood can then determine the difference between cause and effect by using human cell models derived from induced pluripotent stem cells.

Hypothesis: Team Wood hypothesizes that alpha-synuclein oligomers can be used as cellular biomarkers to identify the specific cells where the disease processes begin, thus making their targeted study possible.

Study Design: By detecting the presence of alpha-synuclein oligomers, Team Wood will identify neuronal and non-neuronal cells in the human brain at different stages of disease, which the team will then study using state of the art single cell genomic and transcriptomic methods. This will allow the team to build a comprehensive and detailed picture of the genes and molecular processes that underlie the disease, which the team will then prioritize using network theory and their knowledge of the current and emerging genetic factors. Using a human model system (iPSC), Team Wood will be able to distinguish cause and effect and deliver new targets for therapeutics, diagnostics, and biomarkers of disease.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This interdisciplinary program, combining physical chemistry, computational modeling, genetics, and neurobiology, will allow researchers to much more fully understand the reasons behind why some cells succumb and others resist the pathological processes. Team Wood findings will offer opportunities for accurate markers of disease status, progression, and validated targets for biopharma to develop novel therapies.

Leadership
Nicholas Wood, PhD
COORDINATING LEAD PI

Nicholas Wood, PhD

University College London
Michele Vendruscolo, PhD
CO-INVESTIGATOR

Michele Vendruscolo, PhD

University of Cambridge
Mina Ryten, MD, PhD
Co-Investigator

Mina Ryten, MD, PhD

University College London
Sonia Gandhi, PhD
CO-INVESTIGATOR

Sonia Gandhi, PhD

University College London
Steven Lee, DPhil
CO-INVESTIGATOR

Steven Lee, DPhil

University of Cambridge
Saadia Rahman, MSc
Project Manager

Saadia Rahman, MSc

University College London

Project Outcomes

Team Wood's project addresses the fundamental mechanisms underlying oligomerization of alpha-synuclein and the impact of genetic risk factors in these processes by harnessing single cell transcriptomics and genomics to delineate molecular pathways to disease. View Team Outcomes.

 
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Circuitry and Brain-Body Interactions | 2021

Redefining Parkinson’s Disease Pathophysiology Mechanisms in the Context of Heterogeneous Substantia Nigra Neuron Subtypes

Study Rationale: The motor symptoms of Parkinson’s disease (PD) result from the degeneration of the dopamine-producing neurons in a brain area called the substantia nigra pars compacta (SNc). Recent findings suggest that the SNc is diverse and is comprised of dopamine neurons with distinct properties. How these dopamine neuron “subtypes” contribute to movement, how they are affected in PD, and how they are modified by deep brain stimulation (DBS) remains unknown.

Hypothesis: Team Awatramani will determine whether (a) the SNc is comprised of pro-motor and anti-motor dopamine neuron subtypes and (b) selective loss of pro-motor neurons in PD causes an imbalance in dopamine neuron subtypes that underlies the motor symptoms of PD.

Study Design: Team Awatramani will separate these neurons into their distinct genetic subtypes, which will allow the team to study their specific physiological, anatomical, and functional properties. The team will also determine the molecular and circuit mechanisms underlying the dysfunction of dopamine neurons in a mouse model of PD (LRRK2 model). Additionally, they will explore whether deep brain stimulation of dopamine neuron inputs contributes to the therapeutic efficacy of this treatment.

Impact on Diagnosis: First, Team Awatramani work will identify which dopamine neuron subtypes degenerate and which circuits are dysregulated in PD. This knowledge will be important for understanding the pattern of SNc neuron loss in PD and efficacy of DBS in patients. By using a LRRK2 model, Team Awatramani’s studies also will identify the molecular targets of the hyperactive LRRK2 enzyme, which will be critical for the optimization of LRRK2 inhibitor drugs and their application in patients.

Leadership
Rajeshwar Awatramani, PhD
Coordinating Lead PI

Rajeshwar Awatramani, PhD

Northwestern University
Mark Bevan, PhD
Co-Investigator

Mark Bevan, PhD

Northwestern University
Daniel Dombeck, PhD
Co-Investigator

Daniel Dombeck, PhD

Northwestern University
Thomas Hnasko, PhD
Co-Investigator

Thomas Hnasko, PhD

University of California at San Diego
Loukia Parisiadou, PhD
Co-Investigator

Loukia Parisiadou, PhD

Northwestern University
Amanda Schneeweis
Project Manager

Amanda Schneeweis

Northwestern University

Project Outcomes

Team Awatramani aims to provide a detailed understanding of the diverse dopamine neurons that exist in the substantia nigra in terms of their molecular signatures, unique anatomical circuits, functional contributions to motor behavior, and how this circuitry is disrupted in Parkinson's disease models. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Understanding and Manipulating Cellular and Circuit-Level Vulnerability to Neurodegeneration in Parkinson’s Disease

Study Rationale: Many people with Parkinson’s disease (PD) develop untreatable cognitive symptoms, including problems with attention, decision-making, and dementia at late stages of the disease, due to changes in a crucial part of the brain, the cerebral cortex. Evidence suggests that aggregation of the protein alpha-synuclein in vulnerable nerve cells interferes with their health and damages the cellular networks required for normal brain function. However, the relationships between alpha-synuclein, vulnerable cells, and network activity are not understood. By identifying and understanding the causes and effects of this damage in brain networks, and affected nerve cells and their connections, Team Biederer aims to enable therapies that directly target this disorder.

Hypothesis: Team Biederer hypothesizes that networks of nerve cells in the cortex of the brain become dysfunctional because of damage caused by pathological deposits of the protein alpha-synuclein in vulnerable cells.

Study Design: Team Biederer will assess how alpha-synuclein pathology progressively impairs network function in the brain cortex and identify the features distinguishing vulnerable from resilient cells using innovative technologies, including imaging of activity in the live brain, measurements of attention, profiling of different cell types and their contents, and high-resolution microscopy of neuronal connections. The team will integrate these data using advanced computational methods to design and test cell-specific interventions to restore the function of the disrupted networks. This study will reveal mechanisms of cortical network damage in Parkinson’s disease and will identify the types of nerve cells suited for therapeutic intervention.

Impact on Diagnosis: Diagnostic biomarkers for PD can leverage Team Biederer’s findings of which types of neurons, their connections, and molecular markers are most affected. For treatment, Team Biederer’s work will define novel mechanisms that can directly restore network function by targeting specific types of cortical nerve cells and their connections.

Leadership
Thomas Biederer, PhD
Coordinating Lead PI

Thomas Biederer, PhD

Yale University
Dani Bassett, PhD
Co-Investigator

Dani Bassett, PhD

University of Pennsylvania
Elena Gracheva, PhD
Co-Investigator

Elena Gracheva, PhD

Yale University
Michael Henderson, PhD
Co-Investigator

Michael Henderson, PhD

Van Andel Institute
Michael Higley, MD, PhD
Co-Investigator

Michael Higley, MD, PhD

Yale University
Tina Matos, PhD
Project Manager

Tina Matos, PhD

Yale University

Project Outcomes

Team Biederer's project will gain mechanistic insight into PD pathology linked to progression to dementia. The team will integrate information across molecular, anatomical, and circuit domains, using mathematical modeling, to reveal and manipulate underlying cellular and network vulnerabilities in the cortex. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Circuit Mechanisms for Dopamine Neuron Vulnerability and Resilience in Parkinson’s Disease

Study Rationale: While neurodegeneration in Parkinson’s disease (PD) affects many cells, dopamine neurons are particularly vulnerable, and their loss drives many of the major motor difficulties in PD. To date, the inner workings of the dopamine neurons themselves have been extensively studied to identify sources for this selective vulnerability. However, neurons in the brain are heavily interconnected and interdependent with their surrounding cells and circuitry. Understanding how the “neighborhood” in which dopamine neurons live and function influences their well-being is a critical missing piece in the puzzle of PD.

Hypothesis: Team Calakos hypothesizes that circuit properties of incoming neuronal connections (synapses), surrounding non-neuronal cells (glial cells), and key modulatory cells (those that produce the chemical signal, acetylcholine) contribute to dopamine neuron loss in PD.

Study Design: Team Calakos will evaluate circuit contributions to dopamine neuron dysfunction in PD using state-of-the-art mouse genetic models and patient-derived stem cell models (organoids). Team Calakos members bring unique, specialized expertise that allows the team to isolate and manipulate each of these three components (synapses, glia, and neuromodulators) individually to test its role in dopamine neuron degeneration. In addition to functional manipulations, the team will capture the molecular signatures of the connections dopamine neurons make with each of its “neighbors” to determine which are most disrupted in PD.

Impact on Diagnosis: Recognizing new processes that cause dopamine neuron demise in PD creates new opportunities for intervention. Team Calakos’ bidirectional tests of function may identify not only circuit properties that accelerate disease, but also identify factors that promote resistance to cell death.

Leadership
Nicole Calakos, MD, PhD
Coordinating Lead PI

Nicole Calakos, MD, PhD

Duke University
Cagla Eroglu, PhD
Co-Investigator

Cagla Eroglu, PhD

Duke University
Sergiu Pasca, MD
Co-Investigator

Sergiu Pasca, MD

Stanford University
Scott Soderling, PhD
Co-Investigator

Scott Soderling, PhD

Duke University
Michael Tadross, MD, PhD
Co-Investigator

Michael Tadross, MD, PhD

Duke University
Oula Khoury, PhD
Project Manager

Oula Khoury, PhD

Duke University

Project Outcomes

Team Calakos' collective team efforts will reveal the extent to which circuit components outside of the dopamine neurons themselves can serve as new targets to slow the progression of dopamine neuron death in Parkinson’s disease. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Mapping the Modulatory Landscape Governing Striatal Dopamine Signaling and Its Dysregulation in Parkinson’s Disease

Study Rationale: Nerve cells that produce the brain chemical dopamine die in people with Parkinson’s disease (PD). These nerve cells extend long and thin fibers called axons that release dopamine from thousands of different points, sending signals to other nerve cells in a brain area called the striatum. Many different types of cells and molecules in the striatum can directly control how dopamine is released, but researchers have not yet discovered which ones are the most important and how they are affected in Parkinson’s. By better understanding this cooperation between striatum and the release of dopamine from axons, the team could provide new knowledge toward ways to restore normal function.

Hypothesis: Team Cragg thinks that other molecules in the striatum play a very important role in controlling the release of dopamine, particularly for the types of dopamine axons that are most vulnerable in PD. The team believes that this role is disrupted in the disease and could be targeted to rescue symptoms.

Study Design: Team Cragg’s international team will combine cutting-edge research methods in mice and human cells that allow the team to study the biology behind Parkinson’s. The team will measure dopamine and other signaling molecules in different areas of the striatum and work out what they do. This work will reveal the biological differences between vulnerable and resistant areas. Team Cragg will use this knowledge to study the most promising molecules in mice that develop PD and in cells from people with PD, to then suggest new ways that might fix the problems with dopamine in the disease.

Impact on Diagnosis: Team Cragg’s discoveries will provide knowledge that may help to find new ways of treating Parkinson’s using medicines that target the key signaling molecules in striatum that control dopamine release.

Leadership
Stephanie Cragg, MA, DPhil
Coordinating Lead PI

Stephanie Cragg, MA, DPhil

University of Oxford
Mark Howe, PhD
Co-Investigator

Mark Howe, PhD

Boston University
Peter Magill, DPhil
Co-Investigator

Peter Magill, DPhil

University of Oxford
Konstantinos Meletis, PhD
Co-Investigator

Konstantinos Meletis, PhD

Karolinska Institute
Richard Wade-Martins, MA, DPhil
Co-Investigator

Richard Wade-Martins, MA, DPhil

University of Oxford
Cláudia Mendes, PhD
Project Manager

Cláudia Mendes, PhD

University of Oxford

Project Outcomes

Team Cragg expects their collaboration to unravel the modulators and circuits within striatum that govern dopamine function for vulnerable versus resistant neurons, and the related dysfunction in these key circuits during disease progression, to provide fresh mechanistic rationale for new therapies for Parkinson’s disease. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Dual Role of Neural Activity in Parkinson’s Disease

Study Rationale: Previous work has shown how the loss of dopamine neurons affects brain activity. In this program, Team Edwards will determine how brain activity influences the neurodegeneration that causes Parkinson’s disease (PD). To understand the onset of disease, the team will identify the earliest changes in brain activity and use them to infer the mechanisms involved. Team Edwards will also manipulate activity directly and determine how it interacts with known genes to produce degeneration.

Hypothesis: Team Edwards hypothesizes that abnormalities in neural activity do not simply reflect PD but actually cause the disease. Researchers’ lack of knowledge about the role of neural activity in Parkinson’s makes it difficult to understand how other, identified factors contribute to disease.

Study Design: Team Edwards will use two models of PD, one based on over-expression of the pathogenic protein alpha-synuclein and the other based on a direct increase in activity. The strategy is to (a) identify the earliest events along the pathway to degeneration and to (b) correlate these with the selective vulnerability of particular neurons to PD. These approaches will reveal the processes specifically affected by PD. Team Edwards will also determine how neural activity intersects with factors previously implicated in PD, providing a foundation to understand how they cause degeneration.

Impact on Diagnosis: With greater understanding around the onset of disease, Team Edwards can further investigate how genetic and environmental factors conspire to produce PD. This will open entirely new areas to arrest and prevent the underlying degeneration.

Leadership
Robert Edwards, MD
Coordinating Lead PI

Robert Edwards, MD

University of California at San Francisco
Zayd Khaliq, PhD
Co-Investigator

Zayd Khaliq, PhD

National Institutes of Health
Ken Nakamura, MD, PhD
Co-Investigator

Ken Nakamura, MD, PhD

Gladstone Institutes
Alexandra Nelson, MD, PhD
Co-Investigator

Alexandra Nelson, MD, PhD

University of California at San Francisco
Talia Lerner, PhD
Co-Investigator

Talia Lerner, PhD

Feinberg School of Medicine at Northwestern University
Haru Yamamoto, BA
Project Manager

Haru Yamamoto, BA

University of California at San Francisco

Project Outcomes

By identifying the earliest changes leading to degeneration, the physiology will indicate mechanisms involved in disease onset. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Reconstituting the Lost Nigrostriatal Circuitry in Parkinson’s Disease

Study Rationale: Team Mobley recently discovered that it is possible to generate new neurons to rebuild the damaged neural circuitries in a Parkinson’s disease model. This establishes a new foundation for developing strategies to reverse the disease. Team Mobley’s proposed project will investigate how to change a cell’s identity to encourage it to become a neuron, how to make the right new type of neurons in the brain to rebuild different circuitries, and how to make new neurons that will not become sick again.

Hypothesis: Team Mobley hypothesizes that astrocytes, an abundant population of non-neuronal cells in the brain, store a latent program that allows them to become neurons if the right types of inducing signals are provided.

Study Design: Team Mobley has designed five sets of experiments to address a series of fundamental questions on cell fate determination and reprogramming. The team will analyze individual cells to elucidate key regulatory events responsible for those cells to become neurons. Team Mobley will search for critical genes that make cell fate change less efficient so that the team can improve the reprogramming efficiency by inhibiting the function of those genes. The team will examine reprogramming in different brain regions to test their benefits to both motor and non-motor symptoms and develop strategies to make new and disease-resistant neurons.

Impact on Diagnosis: More information on cellular reprogramming will pave the way to rebuilding the neural circuitries lost to degeneration. If successful, this will lead to the development of a completely new cell replacement therapy against Parkinson’s disease.

Leadership
William Mobley, MD, PhD
Coordinating Lead PI

William Mobley, MD, PhD

University of California at San Diego
Xiang-Dong Fu, PhD
Co-Investigator

Xiang-Dong Fu, PhD

Westlake University
Steven Dowdy, PhD
Co-Investigator

Steven Dowdy, PhD

University of California at San Diego
Allen Wang, PhD
Co-Investigator

Allen Wang, PhD

University of California at San Diego
Yuanchao Xue, PhD
Co-Investigator

Yuanchao Xue, PhD

Chinese Academy of Sciences
Peter Shaw, PhD
Project Manager

Peter Shaw, PhD

University of California at San Diego

Project Outcomes

Team Mobley anticipates that their findings will establish the foundation for developing a cell replacement therapy for the disease based on the initial proof-of-concept study. Once fully developed, the team hopes to be able to effectively reverse the disease phenotype in PD patients. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Gut-to-Brain Circuit Contributions to Parkinson-Like Phenotypes in Disease Models

Study Rationale: Although clinicians have long reported that Parkinson’s disease (PD) does not affect the brain alone, the field has only recently started to investigate gut dysfunction in experimental models of PD. Consequently, the anatomical and functional basis of gut-to-brain circuitry dysfunction in PD—such as network activity and dopamine signaling—remain poorly understood. Team Gradinaru will characterize circuit mechanisms underlying gut-to-brain disease spread and progression in the earliest appearance of Parkinson’s symptoms.

Hypothesis: Team Gradinaru’s hypothesis is that environmental and genetic factors impact the connections between neurons in the enteric nervous system (ENS), which regulates the gastrointestinal tract. This disruption may increase susceptibility to PD triggers—including aggregation of alpha-synuclein, which is toxic to cells and can trigger PD symptoms and gut inflammation. This inflammation could, in turn, augment the toxic form of alpha-synuclein that circulates to the brain and causes dysfunctions in neural circuits and motor deficits.

Study Design: Team Gradinaru will determine PD-relevant gut and brain anatomic and physiologic profiles in rodents, primates, and human cells by clarifying the anatomic pathways underlying gut-to-brain propagation of aggregated alpha-synuclein in mice, and by constructing anatomic and functional maps of macaque ENS and central nervous system PD-relevant circuits at single-cell resolution. The team also will test whether disruption of ENS circuitry mitigates gut-brain disease outcome and evaluate whether spiny mice (a rodent model that can repair damaged tissue) show protection from PD-related gut-brain degeneration.

Impact on Diagnosis: Using powerful new technologies across multiple PD-relevant model systems, this project could uncover novel circuit mechanisms that mediate symptoms, and embolden new therapeutic options to slow, halt, or perhaps reverse peripheral symptoms of PD.

Leadership
Viviana Gradinaru, BS, PhD
Coordinating Lead PI

Viviana Gradinaru, BS, PhD

California Institute of Technology
Andrew Fox, PhD
Co-Investigator

Andrew Fox, PhD

University of California at Davis
Sarkis Mazmanian, PhD
Co-Investigator

Sarkis Mazmanian, PhD

California Institute of Technology
Ashley Seifert, MSc, PhD
Co-Investigator

Ashley Seifert, MSc, PhD

University of Kentucky
David Van Valen, MD, PhD
Co-Investigator

David Van Valen, MD, PhD

California Institute of Technology
Catherine Oikonomou, PhD
Project Manager

Catherine Oikonomou, PhD

California Institute of Technology
Lin Tian, PhD
Collaborating PI

Lin Tian, PhD

Max Planck Florida Institute of Neuroscience

Project Outcomes

This project will use powerful sensor, actuator, and gene delivery technologies across multiple model systems to characterize the anatomical and functional bases of gut-brain circuitry dysfunction in PD, enabling new therapeutic options to slow, halt, or perhaps even reverse peripheral symptoms of PD. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Alpha-Synuclein Effects on Gut-Brain Circuits and Pre-Motor Symptoms in Parkinson’s Disease

Study Rationale: A hallmark of Parkinson’s disease (PD) is the development of abnormal deposits throughout the brain composed of the alpha-synuclein protein. This pathology can be found in the gut too. Increasing evidence indicates that, in some patients, alpha-synuclein pathology may begin in the gut and spread to the brain through a nerve called the vagus, which directly connects the gut to the brain. An animal model developed by Team Kaplitt’s members reproduces many of these features seen in humans to allow study of these pathways and consequences of this advancing disease as it spreads throughout the brain.

Hypothesis: Team Kaplitt hypothesizes that specific vagus nerve cells are responsible for disease spread from gut to brain, with both vagus nerve activity and other factors such as gender and menopause affecting this spread, resulting in early symptoms such as sleep disorders seen in humans before development of movement problems.

Study Design: The first two goals will use genetic manipulation to study (a) what cells may be responsible for gut-to-brain spread of abnormal alpha-synuclein, (b) how disease spread affects normal vagus functions, and (c) how different levels of vagus activity influence disease spread. Team Kaplitt will also study the consequences of this type of gut-brain spread on development of early symptoms that may occur before the movement problems, particularly sleep disorders. Given the reduced risk of PD in women prior to menopause, Team Kaplitt’s final goal is to study these same problems in a novel animal model that mimics human menopause.

Impact on Diagnosis: The gene therapy methods used to block gut-brain spread in Team Kaplitt’s studies could be applied non-invasively to patients with diagnosed presence of gut alpha-synuclein pathology to prevent disease spread. Team Kaplitt’s sleep and menopause studies will further identify opportunities for early intervention and possible hormonal approaches to limiting effects of disease spread.

Leadership
Michael Kaplitt, MD, PhD
Coordinating Lead PI

Michael Kaplitt, MD, PhD

Weill Cornell Medicine
Ted Dawson, MD, PhD
Co-Investigator

Ted Dawson, MD, PhD

Johns Hopkins Medicine
Roberta Marongiu, PhD
Co-Investigator

Roberta Marongiu, PhD

Weill Cornell Medicine
Per Svenningsson, MD, PhD
Co-Investigator

Per Svenningsson, MD, PhD

Karolinska Institute
Eileen Torres, PhD
Project Manager

Eileen Torres, PhD

Weill Cornell Medicine

Project Outcomes

Team Kaplitt anticipates that their findings will advance our collective understanding of how pathology spreads from the gut to the brain in PD, and the consequences of that pathology on early PD symptoms, with the potential for new targeted interventions to block spread and improve neuronal function. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Role of Enteroendocrine Cells in the Origin of Parkinson’s Pathology

Study Rationale: Emerging evidence supports the concept that alpha-synuclein pathology, a hallmark of Parkinson’s disease (PD), might originate in the gastrointestinal tract and spread to the brain. However, where and how pathological alpha-synuclein initially forms remains unclear. Certain gut microbiota and some environmental toxins have been associated with PD. Team Liddle recently discovered that specialized sensory cells in the gut known as enteroendocrine cells (EECs), in direct contact with gut microbiota and different environmental toxins, might transfer misfolded alpha-synuclein to the nervous system in disease.

Hypothesis: Team Liddle hypothesizes that gut microbes and environmental toxins, alone or in combination, corrupt alpha-synuclein protein expressed in EECs to misfolded pathological forms that might spread to the nervous system in a novel circuit important in PD.

Study Design: Using a unique, large, and well-characterized collection of human data, Team Liddle will identify potential triggers and alterations in gut microbiota and neuroinflammatory pathways that are associated with PD. The team will test known and experimental triggers (toxins and microorganisms) in two complementary model systems (ex vivo cultures, and in vivo in mice) to determine effects on the formation and spread of pathological alpha-synuclein within a predictable circuit of interconnected cells vulnerable to disease.

Impact on Diagnosis: These studies will (a) establish how EECs are involved in the formation of pathological alpha-synuclein at the earliest stages of disease, (b) identify gut-associated toxins and microbes that contribute to PD, (c) develop novel “humanized” pre-clinical model systems, and (d) test two particularly promising experimental therapeutic approaches in the novel model systems.

Leadership
Rodger Liddle, MD
Coordinating Lead PI

Rodger Liddle, MD

Duke University
Haydeh Payami, PhD
Co-Investigator

Haydeh Payami, PhD

University of Alabama at Birmingham
Timothy Sampson, PhD
Co-Investigator

Timothy Sampson, PhD

Emory University
Malú Tansey, PhD
Co-Investigator

Malú Tansey, PhD

University of Florida
Andrew West, PhD
Co-Investigator

Andrew West, PhD

Duke University
Senthil Gounder, PhD
Project Manager

Senthil Gounder, PhD

Duke University

Project Outcomes

Team Liddle's project will characterize specialized sensory cells of the gut, known as enteroendocrine cells, as a target for Parkinson’s disease-associated toxicant, gut microbiome, and immune interactions leading to alpha-synuclein pathology, and as a conduit to vagal, enteric, and spinal neurons. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Olfactory Circuits: Alpha-Synuclein-Rich Neurons Respond to Environmental Triggers at the Origin of Parkinson’s Disease

Study Rationale: To slow the progression of Parkinson’s disease (PD), researchers need to know more about how it starts. It is well known now that many individuals with PD have had a significant reduction in their ability to smell years before their movement disorder starts. Here, Team Schlossmacher will study the role of a PD-linked gene, alpha-synuclein, in odor processing, and how viruses in the nose may change how alpha-synuclein is handled within the odor-signaling cells of the brain in people with PD.

Hypothesis: Team Schlossmacher hypothesizes that certain environmental triggers, including viruses, can start a chain reaction inside the nasal cavity by which a protein called alpha-synuclein begins to form insoluble clumps. This happens inside the nerve circuits that specifically process scent and then gradually spreads further inside the brain, thereby promoting Parkinson’s disease.

Study Design: Team Schlossmacher will first define the normal role of the alpha-synuclein protein in the scent-processing circuits of mice and humans. The team will then answer whether so called Lewy bodies (i.e., alpha-synuclein clumps in nerve cells) contribute to the inability to smell. Third, they will study the areas of the human brain that are responsible for smell, including using MRI imaging. Lastly, Team Schlossmacher will perform studies with nasal fluids from people with PD and introduce these (and viruses) into mice, to see if these start a reaction that cause changes in the mouse olfactory system like what is seen in humans with PD, including loss of smell and changes in the alpha-synuclein protein. The team will see if the inability to smell can progress to motor deficits.

Impact on Diagnosis: This study will delineate what causes the loss of sense of smell in PD. That will help researchers to develop new drugs to treat it and explore new ways to diagnose the disease, hopefully at a stage before the movement symptoms appear. Team Schlossmacher may also gain insights into risk factors for PD, which could lead to strategies to help people reduce their risk. The team will also create new animal models that can be used by others.

Leadership
Michael Schlossmacher, MD
Coordinating Lead PI

Michael Schlossmacher, MD

The Ottawa Hospital
Benjamin Arenkiel, PhD
Co-Investigator

Benjamin Arenkiel, PhD

Baylor College of Medicine
Brit Mollenhauer, MD
Co-Investigator

Brit Mollenhauer, MD

University Medical Center Göttingen (UMG
Maxime Rousseaux, PhD
Co-Investigator

Maxime Rousseaux, PhD

University of Ottawa
Christine Stadelmann, MD
Co-Investigator

Christine Stadelmann, MD

Universität Göttingen
Julianna Tomlinson, PhD
Project Manager

Julianna Tomlinson, PhD

Ottawa Hospital

Project Outcomes

Team Schlossmacher will determine whether environment-a-synuclein interactions and inflammation in the nasal cavity can act as triggers for disease initiation, for a-synuclein aggregate formation and associated neuronal circuit dysfunction, thus informing risk and progression of disease and biomarker development in humans. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Basal Ganglia Networks in Parkinson’s Disease

Study Rationale: People with Parkinson’s disease have long been known to display remarkable motor abilities under special circumstances, such as smooth walking with certain visual or auditory cues. This phenomenon is called paradoxical kinesia. In addition, placebos can be surprisingly effective in treating the motor signs of the disease. Team Strick hypothesizes that a specific neuroanatomical substrate supports paradoxical kinesia and the placebo effect. The team plans to define this substrate and investigate its functional organization.

Hypothesis: Team Strick hypothesizes that a specific neural circuit supports paradoxical kinesia and the placebo effect.

Study Design: Team Strick will use cutting-edge techniques to reveal the two distinct brain circuits that enable the basal ganglia to influence the control of voluntary movement in primates. Next, the team will record the electrical and chemical activity of basal ganglia neurons in the best animal model of Parkinson’s disease. In addition, Team Strick will determine the molecular signatures of basal ganglia neurons that are affected by the disease and those that are left intact. Finally, the team will image neural activity in human subjects affected by the disease to determine the full range of strategies that could be used to improve basal ganglia function.

Impact on Diagnosis: Team Strick’s results could re-shape paradigms for therapeutic development and attempts to influence disease progression. Importantly, the team’s results have the potential to use basal ganglia circuits that are untouched by the disease to promote recovery of more normal motor function..

Leadership
Peter Strick, PhD
Coordinating Lead PI

Peter Strick, PhD

University of Pittsburgh
Scott Grafton, MD
Co-Investigator

Scott Grafton, MD

University of California at Santa Barbara
Helen Schwerdt, PhD
Co-Investigator

Helen Schwerdt, PhD

University of Pittsburgh
William Stauffer, PhD
Co-Investigator

William Stauffer, PhD

University of Pittsburgh
Robert Turner, PhD
Co-Investigator

Robert Turner, PhD

University of Pittsburgh
Andreea Bostan, PhD
Project Manager

Andreea Bostan, PhD

University of Pittsburgh

Project Outcomes

Team Strick's project will perform a multidisciplinary characterization of the networks that link the basal ganglia with the cortical motor areas. The information from the team's studies could lead to new therapeutic targets to delay disease progression and new approaches to ameliorate the motor dysfunction that is so disabling for PD patients. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Distributed Circuit Dysfunction Underlying Motor and Sleep Deficits in a Progressive Model of Parkinson’s Disease

Study Rationale: Parkinson’s disease (PD) begins decades before it compromises the ability to move about in the world and sleep through the night. Understanding how the dysfunction of brain circuits begins and then evolves to cause difficulty in moving and sleeping will allow researchers to diagnose PD earlier—increasing the chances of halting disease progression—and to better treat the disease once it appears.

Hypothesis: The progressive damage to dopamine-releasing neurons results in staged disruption of neural circuits in larger and larger parts of the brain, ultimately leading to both motor and sleep deficits characteristic of PD.

Study Design: Team Surmeier’s plan is to study a new genetically engineered mouse model that manifests a progressive, levodopa-responsive parkinsonism. Importantly, this mouse faithfully reproduces the human staging of pathology in key brain circuits. Using the most advanced methods available for studying and manipulating genetically defined brain circuits, the causal linkage between circuit dysfunction and motor and sleep behavior will be determined. 

Impact on Diagnosis: A better understanding of how the circuit dysfunction underlying PD is staged should allow earlier diagnosis—enhancing the potential benefit of disease-modifying therapies—and better treatment strategies for later-stage patients.

Leadership
D. James Surmeier, PhD
Coordinating Lead PI

D. James Surmeier, PhD

Northwestern University
Silvia Arber, PhD
Co-Investigator

Silvia Arber, PhD

University of Basel
Rui Costa, PhD, DVM
Co-Investigator

Rui Costa, PhD, DVM

Allen Institute
Yang Dan, PhD
Co-Investigator

Yang Dan, PhD

University of California at Berkeley
Ann Kennedy, PhD
Co-Investigator

Ann Kennedy, PhD

Northwestern University
Chrissy Weber-Schmidt
Project Manager

Chrissy Weber-Schmidt

Allen Institute

Project Outcomes

Team Surmeier's project will provide fundamental insight into the relationship between progressive dopamine depletion and distributed circuit dysfunction underlying motor and sleep symptoms of Parkinson’s disease. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Activity and Connectivity Drive Neuronal Vulnerability and Disease Progression in Parkinson’s Disease

Study Rationale: Specific brain circuits that are highly melanized (build-up of the dark pigment neuromelanin) with age are primarily affected, particularly early, in Parkinson’s disease (PD). Models incorporating this aspect of PD have only been developed recently and show that increased neuromelanin production causes neurodegenerative changes consistent with Parkinson’s. The regulators of cellular neuromelanin metabolism have not been determined, the effect of neuromelanin on normal activity in these pathways has not been defined, the potential for neuromelanin aggregates to increase alpha-synuclein accumulation has not been evaluated, and the impact of extracellular neuromelanin on detrimental inflammatory processes has not been assessed.

Hypothesis: Activity in melanized brain circuits is a dominant factor in the initiation of PD and sustains its progression by seeding pathology in connected regions and providing the stimulus for chronic inflammation. Manipulating neuromelanin production and/or brain circuit activity can ameliorate these deficits. 

Study Design: Parallel experiments will be performed in mice and non-human primates in which neuromelanin production has been induced for comparison with neuromelanin-producing neurons in people with prodromal and early Parkinson’s. To test whether activity in melanized brain circuits is a dominant factor in the initiation of PD, spatiotemporal activity mapping, imaging, and other techniques will be used, and manipulating neuromelanin production and/or brain circuit activity will be assessed as potential treatments. To determine if neurons spread PD pathology through their connectivity, seeding experiments will be performed and impacts on behavior and neurodegeneration assessed. To determine how non-neuronal mechanisms are involved in disease progression, high-resolution microscopy and cell-specific details of changes in extracellular spaces and infiltration of non-neuronal cells into the brain will be assessed.

Impact on Diagnosis: Diagnosis of neuromelanin changes in the brain are already being assessed for their diagnostic potential, but this study will determine their focus and rate of change with respect to neural activity and clinical features. Team Vila will also identify if reducing neuromelanin levels stabilizes pathology and restores brain activity.

Leadership
Miquel Vila, MD, PhD
Coordinating Lead PI

Miquel Vila, MD, PhD

Vall d'Hebron Research Institute (VHIR)
Glenda Halliday, PhD
Co-Investigator

Glenda Halliday, PhD

University of Sydney
Nicola Mercuri, MD
Co-Investigator

Nicola Mercuri, MD

Tor Vergata University
Jose Obeso, MD, PhD
Co-Investigator

Jose Obeso, MD, PhD

Network Center for Biomedical Research in Neurodegenerative Diseases
Matthias Prigge, PhD
Co-Investigator

Matthias Prigge, PhD

Leibniz Institute for Neurobiology
Javier Hoyo, PhD
Project Manager

Javier Hoyo, PhD

Vall d'Hebron Research Institute (VHIR)

Project Outcomes

The project will unravel molecular mechanisms linking brain circuit activity to PD vulnerability, identify brain circuits through which PD pathology spreads across the brain and periphery, establish non-neuronal mechanisms of PD progression and determine whether modulation of neuromelanin levels and/or brain circuit activity can restore PD circuit dysfunction & pathology. View Team Outcomes.

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Circuitry and Brain-Body Interactions | 2021

Cortical Pathophysiology of Parkinsonism

Study Rationale: The outer mantle of the brain, the cerebral cortex, plays a significant role in selecting and controlling movements. Changes in the activity of cortical neurons are key to disorders of movement, especially Parkinson’s disease (PD). It is unknown, however, which specific cell types are involved and how their activity changes during the course of the disease. In these experiments, Team Wichmann will use new technologies to study large groups of specific types of cortical neurons (for example, those that send fibers to the spinal cord) and explore how their activity and morphology change in animal models of chronic PD.

Hypothesis: Team Wichmann’s hypothesis is that groups of cortical neurons that send fibers to the spinal cord—unlike those that send projections to the striatum—start to show abnormal activity and undergo morphological changes in connections that provide inputs to them when parkinsonism develops.

Study Design: Team Wichmann will measure the anatomical and functional characteristics of neurons in the motor cortex in animal models of slowly progressive PD. Optical imaging methods as well as electrophysiologic recordings will allow the team to measure the activity patterns of large groups of individual cortical neurons, while parallel anatomical studies will identify the reshaping of connections to different families of cortical neurons before and during the development of parkinsonism. Computational analysis will allow Team Wichmann to put the findings together in computer simulations that will help them to understand the cortical circuit abnormalities that contribute to PD.

Impact on Diagnosis: A better understanding of how movement problems in PD develop is key to developing more effective methods to control them. Characterizing the abnormalities in specific families of cortical neurons may allow researchers to develop new therapies that target the affected circuits through deep brain stimulation, pharmacologic, or genetic methods.

Leadership
Thomas Wichmann, MD
Coordinating Lead PI

Thomas Wichmann, MD

Emory University
Hong-Yuan Chu, PhD
Co-Investigator

Hong-Yuan Chu, PhD

Van Andel Research Institute
Adriana Galvan, PhD
Co-Investigator

Adriana Galvan, PhD

Emory University
Yoland Smith, PhD
Co-Investigator

Yoland Smith, PhD

Emory University
Johnson Agniswamy, PhD
Project Manager

Johnson Agniswamy, PhD

Emory University

Project Outcomes

The activity and anatomy of neurons in the brain’s outer mantle, the cortex, are abnormal in Parkinson’s disease. Team Wichmann's studies will help researchers to understand which specific cells or connections are involved in parkinsonism. This knowledge may allow researchers to therapeutically target these circuits through stimulation, pharmacologic, or genetic methods. View Team Outcomes.

 

Parkinson’s disease is the second most common neurodegenerative disease after Alzheimer’s.

For too long, people with Parkinson’s disease have suffered without a meaningful therapy to treat its underlying cause.

With rapid advances in areas like genomics, single-cell technologies, and data analytics, we’re at a tipping point to better understand this devastating disease – but we can’t do it alone.

ASAP builds on the significant strides made by the research community, funders, other experts and strategists around the world. With input across sectors and disciplines, we’ve developed a strategic roadmap to collectively tackle field-wide challenges together.

Guiding Principles

ASAP is guided by the belief that research outcomes will be improved through the following principles:

Collaboration

Given the multifactorial nature of Parkinson’s disease, charting a new path will require multidisciplinary cooperation from investigators with and without a previous record of PD research.

Creativity

Philanthropic capital has the most impact in areas that are deemed unpopular, high-risk, or out-of-scope for government funding, requiring creative and thoughtful consideration of research.

Flexibility

As roadmap goals are implemented, we will be responsive to the evolving nature of research and adjust focus as deemed appropriate.

Transparency

To accelerate research, we’ll support the free flow of data and resources within our collaborative network and make findings available to the broader community.

Building the Roadmap

For the last two years, we’ve engaged more than 100 multidisciplinary experts and strategists to inform our strategic roadmap and thoughtfully guide future investments in scientific discovery.

2017

Planning

This meeting brought the ASAP Planning Advisory Council together to kick off the two-year planning process. The Planning Council comprised both PD and non-PD experts from academia, industry, government, and the patient community to guide strategic roadmap development through a multi-disciplinary and multi-stakeholder lens. We focused on candidate scientific themes, as well as opportunities, challenges, and considerations for the path ahead.

Attendees

James Beck, Parkinson’s Foundation

Patrik Brundin, Van Andel Research Institute (VARI)

Marie-Francoise Chesselet, University of California, Los Angeles

Martin Citron, UCB Pharma

Ted Dawson, Johns Hopkins University School of Medicine

Pietro De Camilli, Yale School of Medicine

David Dexter, Imperial College London

Thomas Gasser, German Center for Neurodegenerative Diseases

Magali Haas, Cohen Veterans Bioscience

Karl Kieburtz, University of Rochester Medical Center

Walter Koroshetz, National Institute of Neurological Disease and Stroke

Kelsey Martin, University of California, Los Angeles

Karoly Nikolich, Alkahest

C. Warren Olanow, Mount Sinai School of Medicine

Bernardo Sabatini, Harvard Medical School

Darryle Schoepp, Merck and Company

Todd Sherer, The Micheal J. Fox Foundation for Parkinson’s Research

Andrew Singleton, National Institute on Aging, NIH

Beth Stevens, Harvard Medical School

David Sulzer, Columbia University Medical Center

Development

This meeting convened the ASAP Planning Advisory Council to discuss a framework by which key knowledge gaps within the candidate scientific themes could be addressed. Strategically, it was recommended that we build on known areas (i.e., candidate scientific themes) by filling in the gaps left by public funding and uncover unknown areas through large, unbiased data collection and analysis.

Attendees

James Beck, Parkinson’s Foundation

Patrik Brundin, Van Andel Research Institute (VARI)

Marie-Francoise Chesselet, University of California, Los Angeles

Ted Dawson, Johns Hopkins University School of Medicine

David Dexter, Imperial College London

Thomas Gasser, German Center for Neurodegnerative Diseases

Magali Haas, Cohen Veterans Bioscience

Karl Kieburtz, University of Rochester Medical Center

Walter Koroshetz, National Institute of Neurological Disease and Stroke

Robert Malenka, Stanford University School of Medicine

Kelsey Martin, University of California, Los Angeles

Karoly Nikolich, Alkahest

C. Warren Olanow, Mount Sinai School of Medicine

Bernardo Sabatini, Harvard Medical School

Randy Schekman, University Of California, Berkeley

Darryle Schoepp, Merck and Company

Todd Sherer, The Micheal J. Fox Foundation for Parkinson’s Research

Andrew Singleton, National Institute on Aging, NIH

David Sulzer, Columbia University Medical Center

Huda Zoghbi, Baylor College of Medicine

We hosted over 100 attendees during this reception held at the Society for Neuroscience Annual Meeting. A feature fireside chat between Melissa Stevens of the Milken Institute Center for Strategic Philanthropy, and George Pavlov of the Sergey Brin Family Foundation, publicly introduced the ASAP initiative to the broader neuroscience community, discussed intent and the role that philanthropy can play to propel discovery, and sought feedback from attendees.

2018

Primed with months of advance preparation in working groups, this international workshop brought together over 70 academic and industry investigators, public and private funders, as well as patients and advocates from across disciplines to design conceptual research programs that addressed a prioritized list of knowledge gaps within the selected scientific themes. A discussion of resource and infrastructure needs was a key component of each program.

Attendees

Matthew Ackerman, MBA

Dario Alessi, University of Dundee

James Beck, Parkinson’s Foundation

Elizabeth Bradshaw, Columbia University

Latese Briggs, Milken Institute Center For Stragetig Philanthropy

Katja Brose, Chan Zuckerberg Initiative (CZI)

Patrik Brundin, Van Andel Research Institute (VARI)

Edward Callaway, The Salk Institute

Paul Cannon, 23andMe, Inc.

Honglei Chen, Michigan State University

Joanne Chory, The Salk Institute

Martin Citron, UCB Pharma

Mark Cookson, National Inistitute on Aging (NIA)

Ted Dawson, John Hopkins University School of Medicine

Pietro De Camilli, Yale School of Medicine

Michel Desjardins, University of Montreal

Steve Finkbeiner, University of California San Francisco

Thomas Gasser, German Center of Neurodegenerative Diseases

Viviana Gardinaru, Caltech

Tim Greenamyre, University of Pittsburgh School of Medicine

Magali Haas, Cohen Veterans Bioscience

Erika Holzbaur-Howland, University of Pennsylvania School of Medicine

Elaine Hsiao, University of California, Los Angeles

Anthony Hyman, Max Planck Institute of Molecular Cell Biology and Genetics

H. Shawn Je, Duke-National University of Singapore Medical School

Kirstie Keller, Milken Institute Center For Strategic Philanthropy

Johnathan Kipnis, University of Virginia Medical School

Jeffrey Kordower, Rush Medical College

Dimitri Krainc, Feinberg School of Medicine at Northwestern University

Anatol Kreitzer, University of California, San Francisco

Arnold Kriegstein, University of California, San Francisco

Thomas Kukar, Emory University School of Medicine

Jin Hyung Lee, Stanford University School of Medicine

Shane Liddlelow, New York University Neurosciences Institute

Byungkook Lim, University of California, San Diego

Robert Malenka, Stanford University School of Medicine

Kenneth Marek, Institute of Neurodegenerative Disorders

Kelsey Martin, University of California, Los Angeles

Sarkis Mazmanian, Caltech

Heidi McBride, McGill University

K. Kimberly McCleary, Center of the Milken Institute

Miratul Muqit, University of Dundee

Karoly Nikolich, Alkahest

Alastair Reith, GlaxoSmithKline Pharmaceuticals

Ekemini Riley, Milken Institute Center of Strategic Philanthropy

Randy Schekman, University of California, Berkeley

Clemens Scherzer, Harvard Medical School

John Siebyl, inviCRO, LLC.

Alessandro Sette, La Jolla Institute for Allergy and Immunology

Todd Sherer, The Michael J. Fox Foundation for Parkinson’s Research

Andrew Singleton, National Insititute on Aging, NIH

Frank Soldner, Massachusetts Institute of Technology (MIT)

Benjamin Stecher, Tomorrow Edition Blog

Melissa Stevens, Milken Institute Center for Strategic Philanthropy

David Sulzer, Columbia University Medical Center

D. James Surmeier, Northwestern University

Margaret Sutherland, National Institute for Neurological Disease and Stroke (NINDS)

Caroline Tanner, University of California, San Francisco School of Medicine

Malú Tansey, Emory University School of Medicine

Daniel Wesson, University of Florida College of Medicine

Su-Chun Zhang, Duke-National University of Singapore Medical School

This forum sought to cultivate a learning community of peer funders and program leaders in neuroscience to explore ways that we can all work together to address this neurological disease. We discussed funding priorities and gleaned lessons learned to avoid unnecessary duplication of efforts.

Attendees

James Beck, Parkinson’s Foundation

Niranjan Bose, Gates Ventures

Patrick Brannelly, Rainwater Charitable Foundation

Latese Briggs, Milken Institute Center For Strategic Philanthropy

Katja Brose, Chan Zuckerberg Initiative (CZI)

Rosa Canet-Avilés, Foundation for the NIH

Valerie Conn, Science Philanthropy Alliance

Jonah Cool, Chan Zuckerberg Initiative

Rick Howitz, Allen Institute for Cell Science

Brett Holleman, Van Andel Research Institute

Ehud Isacoff, University of California, Berkeley

John Lehr, Parkinson’s Foundation

Karoly Nikolich, Alkahest

George Pavlov, Bayshore Global Management

Louis Reichardt, Simons Foundation for Autism Research Initiative (SFARI)

Ekemini Riley, Milken Institute Center For Strategic Philanthropy

Amy Rommel, Rainwater Charitable Foundation

Randy Schekman, University of California, Berkeley

Todd Sherer, The Micheal J. Fox Foundation for Parkinson’s Research

Thomas Snyder, Verily Life Sciences

Melissa Stevens, Milken Institute Center For Strategic Philanthropy

Margaret Sutherland, National Institute for Neurological Disease and Stroke (NINDS)

Jason Tung, Science Philanthropy Alliance

2019

Launch ASAP Initative

OUR MISSION:

Accelerating the pace of discovery and informing the path to a cure for Parkinson’s disease through collaboration, research-enabling resources, and data sharing.

OUR VISION:

Collaborative and transparent research processes and environments that deliver faster and better outcomes for Parkinson’s disease.