Grantees

Neuro-immune Interactions

Chronic neuroinflammation has long been implicated in Parkinson’s disease (PD); however, the underlying molecular mechanisms mediating this process remain unknown. The focus across these teams will be to uncover the molecular and cellular contributions of the neuro-immune system in Parkinson’s disease.

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.

Expand to Read More +Collapse to Read Less –
NEURO-IMMUNE INTERACTIONS | 2020

From Cancer Associations to Altered Immunity in the Pathogenesis of Parkinson’s Disease

Study Rationale: Parkinson’s disease is characterized by premature death of dopamine-producing neurons in the brain; cancer is characterized by overgrowth of dividing cells. Despite being very different, Parkinson’s disease and cancer both have immune dysfunctions. Cancer occurs when the immune system fails to safeguard, and immune therapy holds new hope for cancer treatment. Parkinson’s disease has also been related to immune dysregulation. Moreover, Parkinson’s disease and cancer can in fact be caused by the same gene alterations. Two genes, LRRK2 and Parkin, are among such genes.

Hypothesis: We bring together a team of experts in the fields of Parkinson’s disease and cancer to borrow sophisticated approaches from cancer research to collaboratively test a hypothesis that immune dysregulation is the reason why alterations in LRRK2 and Parkin can cause both Parkinson’s disease and cancer, with a focus on Parkinson’s disease in this proposed work.

Study Design: We will use dopamine-producing neurons derived from Parkinson’s disease patient stem cells, mouse models with genetically modified LRRK2 and Parkin to modulate and characterize their immune signatures in both the periphery and the brain. In addition, we will perform immune profiling in samples from patients with Parkinson’s disease or cancer.

Impact on Diagnosis/Treatment of Parkinson’s Disease: The proposed work approaches Parkinson’s disease from a unique angle. The findings will help better understand common molecular mechanisms underlying Parkinson’s disease and cancer. Immune-related molecules and pathways identified may become new therapeutic targets for Parkinson’s disease.

Leadership
Coordinating Lead PI

Xiqun Chen, MD, PhD

Massachusetts General Hospital

Co-Investigator

Michael Schwarzschild, MD, PhD

Massachusetts General Hospital

Co-Investigator

Timothy Chan, MD, PhD

Cleveland Clinic

Co-Investigator

Weiyi Peng, MD, PhD

The University of Houston

Project Outcomes

The findings of the project will advance our understanding of how immune dysregulation triggered by Parkinson’s and cancer-associated genes can lead to degeneration of dopaminergic neurons, and may open new avenues for prevention and therapies for Parkin’s disease.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

Role of PD-related Proteins as Drivers of Disease through Modulation of Innate and Adaptive Immunity

Study Rationale: The hallmark motor impairments in Parkinson’s disease patients are due to the progressive loss of a special type of neuron in the brain using the chemical messenger dopamine. The mechanisms leading to their destruction during disease progression are not well known. An emerging concept in the field of Parkinson’s disease is that the immune system plays a role in the progressive death of these neurons.

Hypothesis: We hypothesize that Parkinson’s disease is initiated years before the emergence of motor dysfunction in response to mechanisms triggered following gut infection with Gram-negative bacteria. This leads to an autoimmune reaction producing specialized immune cells that can reach the brain and attack dopamine-producing neurons.

Study Design: We will study how mutations in proteins associated with Parkinson’s disease (PINK1, Parkin, LRRK2, VPS35 and GBA) affect the function of immune cells in isolated cell culture (in vitro), as well as in mouse models of Parkinson’s disease. In the model, we will characterize how the immune system is stimulated during gut infection to produce cytotoxic T lymphocytes, and how these cells reach the brain and attack dopamine-producing neurons. Similar studies will also be done with immune cells from the blood of Parkinson’s disease patients and neurons derived from stem cells.

Impact on Diagnosis/Treatment of Parkinson's Disease: The involvement of the immune system in Parkinson’s disease suggests that novel types of therapeutic approaches targeting immune cells could be developed to slow the progression of the disease or even prevent it early on before the emergence of motor impairments.

Leadership
Coordinating Lead PI

Michel Desjardins, PhD

University of Montreal

Co-investigator

Heidi McBride, PhD

McGill University

Co-investigator

Jo Anne Stratton, PhD

McGill University

Co-investigator

Louis-Eric Trudeau, PhD

University of Montreal

Co-investigator

Samantha Gruenheid, PhD

McGill University

Project Outcomes

Our project will identify how alterations in the function of Parkinson’s disease related proteins modulate the immune system and the pathological process leading to motor impairments, as well as key cellular processes that can be targeted for therapeutic intervention.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

Tracing the Origin and Progression of Parkinson’s Disease through the Neuro-Immune Interactome

Study Rationale: While inflammation of the brain caused by immune cells has been implicated in Parkinson’s disease (PD), it is unknown whether these cells attacking the brain initiate the disease. Moreover, there is new evidence that bacteria in the gut may actually trigger the immune system leading to disease initiation via the peripheral nerves that connect the gut with the brain. Our studies will integrate cutting-edge technologies in humans and pre-clinical models to determine whether the disease is mediated by immune cells recognizing alpha-synuclein, a key brain protein implicated in PD.

Hypothesis: We hypothesize that in a subset of cases, PD is initiated by an autoimmune event involving recognition of alpha-synuclein in the gut, and that interactions between the immune system and the peripheral and central nervous systems establish the disease in the brain.

Study Design: We propose integrating cutting-edge technologies in neuroimmunology, single cell genomics, gut microbiome, and computational biology to determine at unprecedented depth whether PD has the signature of autoimmune processes and explore how immune reactions initiate a process, from the gut, that spreads through the peripheral nervous system, and finally to the brain where neurodegeneration results in PD. First, we will characterize T cell-mediated autoimmunity in PD; second, we will evaluate the role of the microbiome in the initiation of PD and progression along the gut-to-brain axis; and third, we will define perturbations in the neuro-immune interactome in the PD brain.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This work will reveal fundamental mechanisms that account for the initiation and progression of PD, uncovering disease- and tissue-specific profiles of autoreactive T cells and overall T cell surveillance that will lead to the discover of perturbed immune pathways in PD with potential application in the development of immunomodulatory therapies.

Leadership
Coordinating Lead PI

David Hafler, MD

Yale University

Co-investigator

Noah Palm, PhD

Yale University

Co-investigator

Ramnik Xavier, MD

Broad Institute

Co-investigator

Rui Chang, PhD

Yale University

Co-investigator

Sreeganga Chandra, PhD

Yale University

Project Outcomes

The successful completion of our proposed studies will identify key immune pathways in the onset of Parkinson’s disease and determine whether to proceed with clinical trials using immunomodulatory drugs for the disease; such trials will aim to block the initiation of disease using immunosuppressive drugs in patients at risk of Parkinson’s disease.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

Activation of Transposable Elements as a Trigger of Neuroinflammation in Parkinson’s Disease

Study Rationale: Inflammation is a common event in Parkinson’s disease (PD), but its source remains unclear. There are many candidates that could cause inflammation in the nervous system. One likely candidate involves the activity of transposable elements, which are viral-like gene fragments left over from viral infections. While transposable elements are normally inactive, certain stressors can reactivate these genes, leading to a potential immune response, including inflammation.

Hypothesis: This study will seek to determine whether transposable elements are active in tissues from patients with Parkinson’s disease and whether this activity can induce inflammation in the nervous system.

Study Design: We will first look for evidence of transposable element activity using single-cell RNA sequencing of tissues from people with Parkinson’s disease. This particular experiment will also allow us to determine whether patient cells that show more transposable element activity also show increased signs of inflammation. Because cells of the central nervous system (neurons, astrocytes and microglia) can be grown in a laboratory culture system, we can also test whether manipulations that induce transposable element activity in these cells also causes an immune response that would result in inflammation. This would suggest that blocking transposon activity could block inflammation.

Impact on Diagnosis/Treatment of Parkinson’s Disease: If we can determine that transposable element activity is the trigger for inflammation in the setting of Parkinson’s disease, it would open several unexplored options for treatment. This would enable the targeted development of anti-inflammatory or anti-viral compounds effective against the specific triggers seen in PD patient samples.

Leadership
Coordinating Lead PI

Johan Jakobsson, PhD

Lund University

Co-investigator

Agnete Kirkeby, PhD

University of Copenhagen

Co-investigator

Molly Hammell, PhD

Cold Spring Harbor Laboratory

Co-investigator

Roger Barker, PhD

Cambridge University

Project Outcomes

This project, which investigates an entirely new pathogenic mechanism in PD, has the potential to open up a number of new avenues of PD-research with clear clinical relevance, including both diagnostics and therapeutics.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

Co-Pathologies Drive Neuroinflammation and Progression in PD

Study Rationale: While Parkinson’s disease (PD) is considered a synucleinopathy, the clinical progression of PD is driven by additional pathological proteins such as tau and beta amyloid. Our overarching hypothesis argues that these pathologies, in concert, result in brain inflammation that may be different in character and/or quantity than single pathology states.

Hypothesis: We will test the hypothesis that the induction of co-pathologies will provide more construct and face validity in the context of human disease, and thus be a superior model for the evaluation of future novel therapies.

Study Design: Herein we propose to create novel nonhuman primate models of co-pathology and inflammation through treatment with alpha synuclein preformed fibrils, AAV-tau, and beta amyloid via aging and transgenesis. We will validate these models by comparing our findings to inflammatory processes seen in human brain samples and refine exploration of the mechanisms involved by blocking these pathologies in mice and nonhuman primates using specific immunotherapies.

Impact on Diagnosis/Treatment of Parkinson’s Disease: The failure to have discovered disease modified treatments for PD may in large part be due to the failure to create relevant animal models to test novel therapeutic strategies. Clearly single pathology models do not reflect the multiple pathologies seen in PD. The mouse and nonhuman primate models to be created and validated in this application along with a deep understanding of their downstream inflammatory pathways will provide essential platforms for testing novel therapeutic strategies.

Leadership
Coordinating Lead PI

Jeffrey Kordower, PhD

Rush University Medical Center

Co-investigator

Ashley Harms, PhD

University of Alabama at Birmingham

Co-investigator

Warren Hirst, PhD

Biogen, Inc.

Project Outcomes

Our program will study the influence of co-pathologies that occur in PD, such as tau and beta amyloid, in inflammation and disease progression to guide future combinatorial therapeutic efforts.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

The Genome-Microbiome Axis in the Cause of Parkinson Disease: Mechanistic Insights and Therapeutic Implications from Experimental Models and a Genetically Stratified Patient Population

Study Rationale: Mutations in the gene for glucocerebrosidase (GBA) increase alpha-synuclein expression and are common in Parkinson disease (PD). However, only about a third of people with GBA mutations get PD. Research suggests that the increase in the alpha-synuclein protein associated with PD may come from the gut and travel along nerves that go to the brain. The microbiome environment, including an increase in gut alpha-synuclein and inflammation, may be a causal link between GBA mutations and PD.

Hypothesis: We think that the combination of one’s genetic makeup and microbiome are important in their risk for getting PD. We will look at people with GBA mutations to see if their risk for PD is caused by their gut bacteria, and to see if their bacteria increase alpha-synuclein transport from gut to brain.

Study Design: We will use mouth and fecal samples from people with GBA-PD to identify the bacteria special to them and how these might increase alpha-synuclein and cause PD. We will also use special lab models to study the changes that link the bacteria and inflammation to alpha-synuclein and its spread from the gut to the brain. We will explore methods to change the bacterial composition of the microbiome to see if this can stop alpha-synuclein transport to the brain.

Impact on Diagnosis/Treatment of Parkinson’s Disease: This research may provide insight into which GBA mutations carriers are most likely to get PD and whether bacterial profile changes will alter alpha-synuclein transport. Being able to predict PD onset may allow us to find a treatment window to prevent disease onset altogether. Further, this research may open more avenues for drug repurposing to find compounds that alter microbiome composition in ways that are beneficial for halting alpha-synuclein transport.

Leadership
Coordinating Lead PI

Anthony Schapira, MD

University College London

Co-investigator

Donato Di Monte, MD

German Center for Neurodegenerative Diseases

Co-investigator

Fabio Blandini, MD

IRCCS Mondino Foundation, National Institute of Neurology, Pavia, Italy

Co-investigator

Michela Deleidi, MD, PhD

University of Tübingen

Co-investigator

Stanislav Ehrlich, PhD

National Research Institute for Agriculture, Food and the Environment

Project Outcomes

We will clarify the role of intestinal bacteria in Parkinson disease, understand its interaction with glucocerebrosidase mutations – a genetic cause of the disease, and provide insight into potential new therapeutic targets.

Expand to Read More +Collapse to Read Less –
Neuro-immune Interactions | 2020

Adaptive Immunity in the Etiology and Progression of Parkinson’s Disease

Study Rationale: Research from our team indicates that immune cells may play central roles in the development of Parkinson’s Disease (PD). In PD, certain types of nerve cells can activate specific types of immune cells (known as T cells, which are found in the blood and lymph nodes). These T cells may kill nerve cells in PD patients’ gastrointestinal tract and brain, and the loss of nerve cells contributes to the symptoms of PD. These immunological responses will be studied in animal models and human tissue including the brains of PD patients.

Hypothesis: We propose that, in PD, these activated T cells mistake the body’s normal nerve cells as foreign invaders (autoimmunity) and this error is critical in the initiation of PD. The interactions of T cells with nerve cells underlies the loss of specific neurons in PD, including substantia nigra dopamine neurons.

Study Design: We will determine the steps that occur in T cell activation in PD by examining T cells in blood from PD patients and healthy controls, and in the gut and brain of new mouse models of PD. To examine if these cell types are in human brain, we have developed new methods to detect signals in specific cells in autopsies of PD patients.

Impact on Diagnosis/Treatment of Parkinson’s Disease: The T cells and the molecules they use to interact with nerve cells can be used to identify people with PD before they develop symptoms, to identify ways to predict the progression of PD, treatments optimal for specific patients, and to provide new therapies by blocking steps in immune responses.

Leadership
Coordinating Lead PI

David Sulzer, PhD

Research Foundation for Mental Hygiene, Inc.

Co-Investigator

Ashley Harms, PhD

University of Alabama at Birmingham

Co-Investigator

Cecilia Arlehamn, PhD

La Jolla Institute for Immunology

Co-Investigator

Sarkis Mazmanian, PhD

California Institute of Technology

Project Outcomes

We expect this unique nexus of microbiology, immunology, and neuroscience to make critical contributions to unraveling PD pathogenesis by defining the role of the adaptive immune system, potentially informing the development of novel therapeutic approaches.

This theme focuses on studying the specific genes associated with Parkinson’s disease and how they interact with the human body.