Microglia activation is a pathological hallmark of neurodegenerative diseases (NDs) and dysfunctional neuro-microglia interactions are believed to occur early in disease pathogenesis. Microglia are dynamic and multiple states, or subpopulations, exist in vivo in mice and humans. While all states share common features, each one has a unique transcriptional signature suggesting a specialized function, but this distinctive function remains to be identified for most of them. Disease-associated microglia transcriptional states (DAMs) have been observed in many neurodegenerative disorders, including ALS. However, it is unclear if DAMs are protective or detrimental in disease progression, which signaling factors induce them, and what their function is in pathology. This project aims to directly address these critical gaps of knowledge in the context of ALS.
Using a novel iPSC-based platform to manipulate the genetics and environment of microglia and study specific states (Dolan*,Therrien* et al. bioRxiv 2022), this project will 1) Identify the role of ALS risk genes in DAM signatures, 2) Determine how microglia influence motor neuron health and 3) Compare DAM transcriptional and functional characteristics between ALS and Alzheimer’s Disease (AD). This platform has already identified the expression pattern of ALS risk genes after exposure to specific challenges and characteristics of microglia expressing APOE, a marker of DAMs in AD and ALS.
Comparing how microglia change across multiple neurodegenerative disorders will pinpoint common mechanisms across diseases and highlight specific mechanisms regulating motor neuron health. Finally, the transcriptomics and functional datasets produced will lead to the identification of new pathways and methods to evaluate the progression of ALS patients and provide a wealth of new targets for drug discovery and treatment paradigms.