Abstract

Microglia, the primary resident immune cells in the brain, constantly survey their environment and protect the brain from pathogens, toxins, and pathological aggregates—such as those found in age-associated neurodegenerative diseases like Parkinson’s and Alzheimer’s. The accumulation of misfolded α-synuclein (α-syn) is a hallmark of synucleinopathies, including Parkinson’s disease, where it contributes to the degeneration of dopaminergic neurons in the substantia nigra, leading to characteristic motor and non-motor symptoms. Growing evidence suggests that the accumulation and propagation of α-syn drive disease progression, and microglia play a role in clearing these aggregates and regulating their spread. However, the underlying cellular mechanisms of microglial involvement remain poorly understood.

The goal of this project is to study the dynamic interactions between microglia, neurons, and astrocytes in the context of α-syn aggregation and spreading using a human induced pluripotent stem cell (iPSC)-derived neural triculture model. We will use time-lapse imaging, immunofluorescence, and biochemical assays to track how microglia influence α-syn uptake, intracellular processing, and intercellular transfer. We will use single cell RNA sequencing to dissect cell-type-specific contributions to α-syn pathology, by which we may identify potential key pathways that regulate a-syn propagation. Finally, we will manipulate the potential pathway in microglia using pharmacological inhibitor to assess their effects on α-syn uptake, aggregation, and spreading. These findings will help identify potential targets for therapeutic intervention.