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.
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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: Team Chen brings 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: Team Chen 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, the team 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
Project Outcomes
The findings of the project will advance Team Chen's 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 Parkinson’s disease. View Team Outcomes.
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: Team Desjardins hypothesizes 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: Team Desjardins 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, the team 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
Project Outcomes
Team Desjardins' 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. View Team Outcomes.
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. Team Hafler’s 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: Team Hafler hypothesizes 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: Team Hafler proposes 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, Team Hafler will characterize T cell-mediated autoimmunity in PD; second, the team will evaluate the role of the microbiome in the initiation of PD and progression along the gut-to-brain axis; and third, they 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
Project Manager
Nick Buitrago-Pocsangre, MSc
Yale University
Project Outcomes
The successful completion of Team Hafler's 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. View Team Outcomes.
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: Team Jakobsson 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 the team 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, Team Jakobsson 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 Team Jakobsson 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
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. View Team Outcomes.
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. Team Kordower’s 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: Team Kordower 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 Team Kordower proposes 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. Team Kordower will validate these models by comparing their 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
Project Outcomes
Team Kordower's 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. View Team Outcomes.
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: Team Schapira thinks that the combination of one’s genetic makeup and microbiome are important in their risk for getting PD. The team 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: Team Schapira 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. The team 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. Team Schapira 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 Team Schapira 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
Project Outcomes
Team Schapira 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. View Team Outcomes. View Team Outcomes.
Neuro-immune Interactions | 2020
Adaptive Immunity in the Etiology and Progression of Parkinson’s Disease
Study Rationale: Research from Team Sulzer 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: Team Sulzer proposes 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: Team Sulzer 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, Team Sulzer has 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
Project Outcomes
Team Sulzer expects 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. View Team Outcomes.
The ASAP Collaborative Research Network spans beyond neuro-immune interactions. Check out the circuitry and functional genomics themes for a complete look at the work our diverse group of grantees is doing to tackle key knowledge gaps in Parkinson’s disease research.