Neuroinflammation, Genomic Regulation, and Systemic Drivers

Five Fellows have projects exploring the role of the immune system, environmental factors, and non-neuronal cells in Parkinson’s disease pathogenesis. Specific topics examine interactions between Parkinson’s disease-linked genetic vulnerability and the immune response, how alpha-synuclein pathology affects immune response, and the influence of inflammation on dopaminergic activity. By studying how the microbiome, genetics, and overlooked cell types trigger inflammation and drive cell death, these researchers forge a path for immune-targeted therapies and new approaches in precision medicine.

M. Elizabeth Deerhake, MD, PhD

Project Title: Identifying common, non-coding genetic drivers of neuroinflammation in Parkinson’s disease

Home Team: Hafler (Hafler Lab)

Host Team: Scherzer (Scherzer Lab)

Institution: Yale University

Project Summary: This project aims to uncover the role of neuroinflammation in Parkinson’s disease by identifying non-coding genetic variants regulating gene expression in innate immune cells. A massively parallel report assay (MPRA) will screen thousands of Parkinson’s disease-associated variants for regulatory activity in macrophages. Next, the Scherzer lab’s Parkinson5D Atlas will be used to identify variants with in vivo allele-specific regulatory effects in brain macrophages, microglia, and monocytes. Integrating experimental and computational findings, this project will map the expression of target genes across brain regions and disease stages. This work will advance Parkinson’s disease research by prioritizing genetically supported neuroimmune pathways.

James Evans, PhD

Project Title: Oligodendrocyte-driven innate and adaptive inflammation in Parkinson’s disease

Home Team: Wood (Gandhi Lab)

Host Team: Studer (Khurana Lab)

Institution: University College London

Project Summary: Parkinson’s disease is defined by dopaminergic neuronal loss and alpha-synuclein aggregates in Lewy bodies. However, evidence from genetics and single-cell transcriptomics indicates a substantial oligodendroglial component, and data suggest alpha-synuclein oligomers drive a pro-inflammatory oligodendrocyte state. Yet, mechanisms by which oligodendrocyte-specific inflammation propagates to immune cells and impacts neuronal health remain unknown. This project will employ iPSC-derived oligodendrocyte and co-culture paradigms, alongside patient T cells, to investigate how alpha-synuclein-induced oligodendrocytes influence glia, neurons, and T cells. Investigating oligodendrocyte-mediated crosstalk and disease-specific T cell responses enables the definition of blood-based immune signatures relevant for patient stratification in Parkinson’s disease.

Amandine Even, PhD

Project Title: Exploring the role of glia and T cells in the fatal outcome of vulnerable neurons in Parkinson’s disease

Home Team: Desjardins (Trudeau Lab)

Host Team: Schapira (Deleidi Lab)

Institution: University of Montreal

Project Summary: Inflammation is a hallmark of Parkinson’s disease and may exacerbate intrinsic neuronal vulnerability. This project will test whether systemic inflammation modulates dopaminergic and noradrenergic neuronal activity using in vivo fiber photometry and patient-derived iPSC cocultures. Furthermore, innovative quadripartite iPSC cocultures (neurons, astrocytes, microglia, and T cells) will be used to examine how these cell types interact to drive selective neuronal vulnerability. Finally, a brain-chip model will examine how patient-derived glia influence T cell infiltration. This integrated approach, distinguishing early functional alterations from degeneration, will clarify mechanisms linking inflammation to neuronal loss and reveal potential novel therapeutic targets in Parkinson’s disease.

Alexandra Kazanova, PhD

Project Title: Unravelling the impact of the microbiome on motor dysfunction in Parkinson’s disease using phenotypic heterogeneity in the Pink1-/- infection-induced disease model

Home Team: Desjardins (Gruenheid Lab)

Host Team: Sulzer (Mazmanian Lab)

Institution: McGill University

Project Summary: Development of Parkinson’s disease involves genetic and environmental factors. The microbiome and intestinal inflammation have both been implicated as environmental triggers in genetically susceptible individuals. Previous work has shown that gastrointestinal infection of mice with genetic Parkinson’s disease susceptibility (Pink1-/-) causes dopamine-sensitive motor impairments. However, about 30% of these mice, despite a similar course of infection, do not develop motor phenotypes, suggesting a role for additional factors in disease progression. Recent work found that the development of disease in this model depends on gut microbiome composition. This project will leverage this novel system to characterize how the microbiome interacts with genetic Parkinson’s disease susceptibility to trigger disease.

Indrani Poddar, PhD

Project Title: The pathogenic role of neuronal DNA-sensing cGAS–STING pathway in alpha-synucleinopathy

Home Team: Lee (Lee Lab)

Host Team: Studer (Khurana Lab)

Institution: University of Minnesota

Project Summary: Parkinson’s disease and other alpha-synucleinopathies are characterized by neuronal aggregation of alpha-synuclein. Previous work has shown that neurons with alpha-synuclein aggregates show activation of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) cascade, including the substantia nigra dopaminergic neurons. Although the cGAS-STING pathway has been implicated in Parkinson’s disease, it is thought that the activation occurs in glial cells. Thus, the significance of neuronal cGAS-STING activation remains unexplored. The main goal of this proposal is to define how alpha-synuclein pathology leads to DNA damage and the cGAS-STING response in different types of human neurons, leading to inflammation and neurodegeneration.