CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.
CRISPR screening in neurodegeneration and lysosomal biology: Uncovering disease mechanisms and genetic modifiers.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Bethesda, US · Author affiliation
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States of America.Location evidence
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Original abstract
Growing genetic and mechanistic evidence has highlighted substantial convergence between neurodegenerative disorders and lysosomal biology. Variants in lysosomal protein-encoding genes associated with lysosomal storage disorders (LSDs) have been implicated in common neurodegenerative diseases, suggesting that perturbations of lysosomal function represent a shared pathogenic mechanism. However, the low penetrance of neurodegenerative diseases in individuals carrying variants in these lysosomal genes suggests that additional genetic modifiers are involved as well. Advances in functional genomics, particularly clustered regularly interspaced short palindromic repeat (CRISPR)-based high-throughput screens, have opened new avenues to identify such modifiers and elucidate disease-associated pathways. These unbiased approaches have accelerated the discovery of molecular mechanisms underlying neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Although to date few studies have applied CRISPR-based functional screens directly to LSDs, findings from neurodegenerative disease models provide a valuable framework for investigating lysosomal pathways and identifying genetic factors that influence phenotypic variability. In this review, we summarize recent advances in in vitro CRISPR-based screening approaches in neurodegenerative disorders and discuss their implications for understanding lysosomal biology and LSD-related mechanisms.