Identifying shared and distinct cell type vulnerability across neurological diseases.

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PROJECT SUMMARY A central question in neurodegeneration research is to identify type-specific changes associated with the onset and progression of neurological disease. Currently, studying alterations in cell type composition, signatures, and function in response to pathology are areas of active investigation in Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS- FTD) research. For polygenic diseases such as AD, PD, and ALS-FTD, genome-wide association, bulk tissue transcriptomics, and bulk proteomics studies have highlighted candidate loci, genes, and proteins with significant associations to pathological and clinical manifestations of diseases. However, these efforts are focused separately on each disease; thus, the major gap is a lack of studies that systematically examine tissue from the same brain regions from individuals with different neurodegenerative diseases. Here, we aim to contextualize disease-specific bulk tissue findings using cutting-edge techniques at single-cell resolution to characterize commonalities and differences in cell type-specific changes across different neurodegenerative diseases. Such cross-disease investigation is likely to shed light on each disease individually, by linking specific cell type changes to pathologies that are hallmarks for a particular neurodegenerative disease. In parallel with data generation and analysis, we also aim to create a standardized, cross-disease interactive portal for investigators to explore not only cell type-specific signatures that are associated with individual neurodegenerative diseases like AD, but also signatures that are shared between AD and other diseases. This approach will not only further our understanding of AD-specific cell type vulnerability, but also distinguish between specific and general signatures of neurodegeneration in multiple other diseases. Thus, our overall goals are not only to create a foundational data set to refine our understanding of cell type vulnerability and alteration within AD and across other neurodegenerative diseases, but also to establish a robust framework to allow external researchers to derive new disease-specific insights into cell type composition changes in neurodegeneration.