Role of Senataxin in Amyotrophic Lateral Sclerosis

J Mol Neurosci. 2023 Dec;73(11-12):996-1009. doi: 10.1007/s12031-023-02169-0. Epub 2023 Nov 20.


Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.

Keywords: Amyotrophic lateral sclerosis (ALS); Motor neurons (MNs); Sen1; Senataxin (SETX).

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis* / metabolism
  • DNA Helicases / genetics
  • Gene Expression Regulation
  • Humans
  • Motor Neurons / metabolism
  • Multifunctional Enzymes / genetics
  • Multifunctional Enzymes / metabolism
  • Mutation
  • RNA Helicases / genetics
  • RNA Helicases / metabolism


  • SETX protein, human
  • DNA Helicases
  • RNA Helicases
  • Multifunctional Enzymes