Alternative splicing in neurodegenerative disease and the promise of RNA therapies

Alternative splicing dysregulation contributes to the molecular pathology of a wide range of neurodegenerative diseases. In this Review, Nikom and Zheng discuss the latest advances in RNA-based therapeutic strategies developed to target the underlying splicing mechanisms. Alternative splicing generates a myriad of RNA products and protein isoforms of different functions from a single gene. Dysregulated alternative splicing has emerged as a new mechanism broadly implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson disease and repeat expansion diseases. Understanding the mechanisms and functional outcomes of abnormal splicing in neurological disorders is vital in developing effective therapies to treat mis-splicing pathology. In this Review, we discuss emerging research and evidence of the roles of alternative splicing defects in major neurodegenerative diseases and summarize the latest advances in RNA-based therapeutic strategies to target these disorders.