Decoding neurodegeneration one cell at a time

Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.