RNA Is a Double-Edged Sword in ALS Pathogenesis

Benjamin L. Zaepfel, Jeffrey D. Rothstein

Research output: Contribution to journalReview articlepeer-review


Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects upper and lower motor neurons. Familial ALS accounts for a small subset of cases (<10–15%) and is caused by dominant mutations in one of more than 10 known genes. Multiple genes have been causally or pathologically linked to both ALS and frontotemporal dementia (FTD). Many of these genes encode RNA-binding proteins, so the role of dysregulated RNA metabolism in neurodegeneration is being actively investigated. In addition to defects in RNA metabolism, recent studies provide emerging evidence into how RNA itself can contribute to the degeneration of both motor and cortical neurons. In this review, we discuss the roles of altered RNA metabolism and RNA-mediated toxicity in the context of TARDBP, FUS, and C9ORF72 mutations. Specifically, we focus on recent studies that describe toxic RNA as the potential initiator of disease, disease-associated defects in specific RNA metabolism pathways, as well as how RNA-based approaches can be used as potential therapies. Altogether, we highlight the importance of RNA-based investigations into the molecular progression of ALS, as well as the need for RNA-dependent structural studies of disease-linked RNA-binding proteins to identify clear therapeutic targets.

Original languageEnglish (US)
Article number708181
JournalFrontiers in Cellular Neuroscience
StatePublished - Jul 19 2021


  • FTD
  • FUS
  • RNA
  • TDP43
  • amyotrophic lateral sclerosis

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience


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