Grantees

Biology of PD-associated Genes

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.

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Biology of PD-associated Genes | 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. We aim to combine the complementary expertise of our four research laboratories to perform fundamental, state-of-the-art experimentation to better comprehend the biology that is controlled by LRRK2. Our 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. We aim 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: We showed that mutant LRRK2 triggers a series of molecular changes that cause new sets of proteins to interact. Our 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: Our findings will provide novel, fundamental information of relevance to understanding the origin and progression of Parkinson’s that we hope will lead to new ideas to better diagnose, treat, and even prevent this malady in the future.

Leadership
Coordinating Lead PI

Dario Alessi, PhD

University of Dundee

Co-Investigator

Miratul Muqit, MD, PhD

University of Dundee

Co-Investigator

Monther Abu-Remaileh, PhD

Stanford University

Co-Investigator

Suzanne Pfeffer, PhD

Stanford University

Project Outcomes

Our project will provide fundamental information regarding how mutations in LRRK2 cause Parkinson's disease.

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Biology of PD-associated Genes | 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, our research will help to identify new opportunities for reversing the vulnerabilities that cause the disease.

Hypothesis: We hypothesize 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: We 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, we hope 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
Coordinating Lead PI

Pietro De Camilli, MD

Yale University

Co-investigator

Kallol Gupta, PhD

Yale School of Medicine

Co-investigator

Karin Reinisch, PhD

Yale School of Medicine

Co-investigator

Shawn Ferguson, PhD

Yale School of Medicine

Co-investigator

Timothy Ryan, PhD

Weill Cornell Medical School

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.

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Biology of PD-associated Genes | 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. We believe that by understanding the genetics and the mechanistic basis of this variability, we will be able to design therapies to slow Parkinson’s progression. We have 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. We 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: We want 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, we will find genes that influence the progression of parkinsonism, and then assess the mechanisms by which they affect disease development. We have already found that GBA and LRRK2 influence clinical rates of decline so we 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
Coordinating Lead PI

John Hardy, PhD

University College London

Co-investigator

Frances Platt, PhD

University of Oxford

Co-investigator

Maria Spillantini, PhD

Cambridge University

Co-investigator

Mina Ryten, MD, PhD

University College London

Co-investigator

Zane Jaunmuktane, MD

University College London

Project Outcomes

We 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.

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Biology of PD-associated Genes | 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, we 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. We 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: Our 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
Coordinating Lead PI

J. Wade Harper, PhD

Harvard University

Co-Investigator

Ruben Fernandez-Busnadiego, PhD

University of Gottingen Medical Center

Co-Investigator

Judith Frydman, PhD

Stanford University

Co-Investigator

Franz-Ulrich Hartl, MD

Max Planck Institute of Biochemistry, Martinsried

Co-Investigator

Brenda Schulman, PhD

Max Planck Institute of Biochemistry, Martinsried

Project Outcomes

Through biochemical reconstitution, in situ structural analysis, and genetic perturbations, our 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.

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Biology of PD-associated Genes | 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 us 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 we know how they work together, we hope to figure out how to make them work faster and better, so that we can prevent Parkinson's disease from ever starting.

Study Design: We think of PINK1, parkin and the proteins of mitophagy as nanomachines. We call our type of research "mechanistic" because it seeks to understand how these machines work. We rely heavily on the most powerful light and electron microscopes available, and we 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: Our dream is to understand PINK1, parkin and mitophagy so well that we 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
Coordinating Lead PI

James Hurley, PhD

University of California, Berkeley

Co-investigator

Erika Holzbaur, PhD

University of Pennsylvania

Co-investigator

Eunyong Park, PhD

University of California, Berkeley

Co-investigator

Michael Lazarou, PhD

Monash University

Co-investigator

Sascha Martens, Dr rer nat

Max Perutz Labs, University of Vienna

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.

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Biology of PD-associated Genes | 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. Here we 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 know 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 us 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: Our ability to design better treatments for Parkinson’s is directly related to our 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
Coordinating Lead PI

Deniz Kirik, MD, PhD

University of Sydney

Co-investigator

Carolyn Sue, PhD

Kolling Institute, Royal North Shore Hospital, University of Sydney

Co-investigator

Clare Parish, PhD

Florey Institute of Neuroscience & Mental Health, The University of Melbourne

Co-investigator

Jennifer Johnston, PhD

NysnoBio LLC

Co-investigator

Lachlan Thompson, PhD

Florey Institute of Neuroscience & Mental Health, The University of Melbourne

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.

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Biology of PD-associated Genes | 2020

Senescence in Parkinson’s Disease and Related Disorders

Study Rationale: While aging is the greatest risk factor for 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, we will use novel mouse models of premature senescence to test whether premature senescence in specific cell types causes PD-like neuropathology. Second, we will combine mouse models of senescence and familial PD to test whether senescence participates in neuropathology caused by mutant PD-linked genes. Specifically, we will determine if pathology in a PD mouse model causes premature senescence and whether removing senescent cells from brain can prevent PD pathology. Finally, we 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: Our 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, our studies may identify new biomarkers of senescence in PD.

Leadership
Coordinating Lead PI

Michael Lee, PhD

University of Minnesota

Co-investigator

Darren Moore, PhD

Van Andel Institute

Co-investigator

Jose Bras, PhD

Van Andel Institute

Co-investigator

Laura Niedernhofer, MD, PhD

University of Minnesota

Project Outcomes

Our 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.

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Biology of PD-associated Genes | 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, we 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: We recently discovered that chains of the LRRK2 protein can wrap around cellular highways called “microtubules”. Our work suggests that LRRK2 blocks the cellular machines that move on these highways. We will explore the idea that mutations in LRRK2 cause PD by acting as roadblocks that change the normal transport of chemical information inside cells. We will test additional ideas that arise from the experiments we perform.

Study Design: Our 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. We will use our expertise to solve structures of multiple conformations and variants of LRRK2 to manipulate these different pools of LRRK2 and understand their cellular functions. We will determine how LRRK2 binds to microtubules and affects microtubule-based motors. We 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. We expect our work will reveal what LRRK2 looks like, what it does in cells, and why its malfunction causes PD. Our work will be critical for the design of drugs targeting LRRK2.

Leadership
Coordinating Lead PI

Samara Reck-Peterson, PhD

University of California, San Diego

Co-investigator

Andres Leschziner, PhD

University of California, San Diego

Co-investigator

Elizabeth Villa, PhD

University of California, San Diego

Co-investigator

Florian Stengel, PhD

University of Konstanz

Co-investigator

Stefan Knapp, PhD

Goethe-Universität

Project Outcomes

Our 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.

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Biology of PD-associated Genes | 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. We 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, we hope to identify new ways to detect and treat the disease in the future.

Hypothesis: We hypothesize that combining complex human cell culture models such as 3-dimensional brain organoids with sophisticated genome-scale functional analysis will allow us 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: We 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, we will decipher the key molecular signatures that contribute to Parkinson’s disease. Once identified, we 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
Coordinating Lead PI

Donald Rio, PhD

University of California

Co-investigator

Dirk Hockemeyer, PhD

UC Berkeley

Co-investigator

Frank Soldner, MD

Albert Einstein College of Medicine

Co-investigator

Helen Bateup, PhD

University of California, Berkeley

Co-investigator

Luke Gilbert, PhD

University of California, San Francisco

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.

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Biology of PD-associated Genes | 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? We do not know how disease-associated variants cause neurodegeneration and why they impair some brain cells but not others. Our 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: We hypothesize that most GWAS variants function through cell-, space-, and stage-dependent gene-regulatory mechanisms.

Study Design: Here we 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). We 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: Our 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
Coordinating Lead PI

Clemens Scherzer, MD

Harvard Medical School, Brigham & Women's Hospital

Co-investigator

Joshua Levin, PhD

Broad Institute

Co-investigator

Mel B. Feany, MD, PhD

Harvard Medical School, Brigham & Women's Hospital

Co-investigator

Su-Chun Zhang, MD, PhD

University of Wisconsin-Madison

Co-investigator

Xianjun Dong, PhD

Harvard Medical School, Brigham & Women's Hospital

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.

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Biology of PD-associated Genes | 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, we still cannot confidently answer this question, or explain how certain cells in our 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: We hypothesize 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 we propose 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 our team, we will convert these stem cells into the different types of brain cells implicated in PD — neurons, microglia, and astrocytes — allowing us to investigate how genetic risk factors, the aging process, and these different cell types interact to trigger disease. We 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
Coordinating Lead PI

Lorenz Studer, MD

Memorial Sloan Kettering Cancer Center

Co-investigator

Gist Croft, PhD

New York Stem Cell Foundation

Co-investigator

Jian Peng, PhD

University of Illinois at Urbana-Champaign

Co-investigator

Joseph Powell, PhD

Garvan Institute for Medical Research

Co-investigator

Vikram Khurana, MD, PhD

Harvard Medical School

Project Outcomes

Our 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.

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Biology of PD-associated Genes | 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. We 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: We hypothesize 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, we will investigate the molecular architecture of polyamine and glucosylceramide transporters and identify mechanisms to modulate their activity. Second, we 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, we 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, we will collect evidence for disturbed polyamine and glucosylceramide transport in PD patients.

Impact on Diagnosis/Treatment of Parkinson’s Disease: We 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. We will analyze whether alterations in the polyamine and glucosylceramide levels together may be considered as biomarkers for PD.

Leadership
Coordinating Lead PI

Peter Vangheluwe, PhD

Katholieke Universiteit Leuven

Co-Investigator

Tim Ahfeldt, PhD

Icahn School of Medicine at Mount Sinai, NY

Co-Investigator

Ellen Sidransky, MD

National Human Genome Research Institute, US

Co-Investigator

Joseph Lyons, PhD

University of Aarhus, DK

Co-Investigator

Veerle Baekelandt, PhD

Katholieke Universiteit Leuven

Project Outcomes

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

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Biology of PD-associated Genes | 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 our brain, but also of our 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: We hypothesize 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: We will use the expertise of our 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 us 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. We will next analyze how these DNA variants change the functioning of these specific cell types, by using our 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
Coordinating Lead PI

Thierry Voet, PhD

University of Leuven

Co-investigator

Bernard Thienpont, MD, PhD

University of Leuven

Co-investigator

Christos Proukakis, PhD

University College London

Co-investigator

Guy Boeckxstaens, MD, PhD

University of Leuven

Co-investigator

Stein Aerts, PhD

VIB-University of 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 ageing and in PD, we will advance our understanding of the etiopathogenesis of the disease and pave the path for devising new treatment modalities.

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Biology of PD-associated Genes | 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, we use alpha-synuclein oligomers as a cellular biomarker to identify the right cells. We will then apply state-of-the-art genomic and genetic analyses to identify genes and proteins that form the disease pathways. We can then determine the difference between cause and effect by using human cell models derived from induced pluripotent stem cells.

Hypothesis: We hypothesize 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, we will identify neuronal and non-neuronal cells in the human brain at different stages of disease, which we will then study using state of the art single cell genomic and transcriptomic methods. This will allow us to build a comprehensive and detailed picture of the genes and molecular processes that underlie the disease, which we will then prioritize using network theory and our knowledge of the current and emerging genetic factors. Using a human model system (iPSC) we 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 modelling, genetics and neurobiology, will allow us to much more fully understand the reasons behind why some cells succumb and other resist the pathological processes. Our findings will offer opportunities for accurate markers of disease status, progression, and validated targets for biopharma to develop novel therapies.

Leadership
Coordinating Lead PI

Nicholas Wood, PhD

University College London

Co-investigator

Michele Vendruscolo, PhD

University of Cambridge

Co-investigator

Mina Ryten, MD, PhD

University College London

Co-investigator

Sonia Gandhi, PhD

Francis Crick Institute

Co-investigator

Steven Lee, DPhil

University of Cambridge

Project Outcomes

Our 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.

 

This theme focuses on ability of the nervous system to sense environmental stimuli and relay those signals to immune cells.