Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies

Simple Summary Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases, cause immense suffering to patients and their families. Despite an urgent need for therapies, they are still lacking, partly due to an incomplete understanding of the mechanisms involved. For example, it is unknown why specific brain regions are affected while others are not, a feature known as selective vulnerability. A better understanding of how certain regions resist disease, while others fail, could lead to new therapies. This review discusses ten studies that analyze gene expression changes in specific brain cell types as they respond to the early stages of four types of neurodegenerative disease. It concludes with a summary of recurring themes that address questions about the mechanisms behind selective vulnerability.Abstract Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.