Polyglutamine spinocerebellar ataxias: emerging therapeutic targets

Expert Opin Ther Targets. 2020 Nov;24(11):1099-1119. doi: 10.1080/14728222.2020.1827394. Epub 2020 Oct 10.


Introduction: Six of the most frequent dominantly inherited spinocerebellar ataxias (SCAs) worldwide - SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17 - are caused by an expansion of a polyglutamine (polyQ) tract in the corresponding proteins. While the identification of the causative mutation has advanced knowledge on the pathogenesis of polyQ SCAs, effective therapeutics able to mitigate the severe clinical manifestation of these highly incapacitating disorders are not yet available.

Areas covered: This review provides a comprehensive and critical perspective on well-established and emerging therapeutic targets for polyQ SCAs; it aims to inspire prospective drug discovery efforts.

Expert opinion: The landscape of polyQ SCAs therapeutic targets and strategies includes (1) the mutant genes and proteins themselves, (2) enhancement of endogenous protein quality control responses, (3) abnormal protein-protein interactions of the mutant proteins, (4) disturbed neuronal function, (5) mitochondrial function, energy availability and oxidative stress, and (6) glial dysfunction, growth factor or hormone imbalances. Challenges include gaining a clearer definition of therapeutic targets for the drugs in clinical development, the discovery of novel drug-like molecules for challenging key targets, and the attainment of a stronger translation of preclinical findings to the clinic.

Keywords: Polyglutamine spinocerebellar ataxias; ataxin; drug discovery; polyQ tract; polyglutamine tract; therapeutic targets.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Drug Development
  • Drug Discovery
  • Humans
  • Molecular Targeted Therapy*
  • Oxidative Stress
  • Peptides / metabolism*
  • Spinocerebellar Ataxias / drug therapy*
  • Spinocerebellar Ataxias / physiopathology


  • Peptides
  • polyglutamine