HD and SCA1: Tales from two 30-year journeys since gene discovery

Neuron. 2023 Nov 15;111(22):3517-3530. doi: 10.1016/j.neuron.2023.09.036. Epub 2023 Oct 19.

Abstract

One of the more transformative findings in human genetics was the discovery that the expansion of unstable nucleotide repeats underlies a group of inherited neurological diseases. A subset of these unstable repeat neurodegenerative diseases is due to the expansion of a CAG trinucleotide repeat encoding a stretch of glutamines, i.e., the polyglutamine (polyQ) repeat neurodegenerative diseases. Among the CAG/polyQ repeat diseases are Huntington's disease (HD) and spinocerebellar ataxia type 1 (SCA1), in which the expansions are within widely expressed proteins. Although both HD and SCA1 are autosomal dominantly inherited, and both typically cause mid- to late-life-onset movement disorders with cognitive decline, they each are characterized by distinct clinical characteristics and predominant sites of neuropathology. Importantly, the respective affected proteins, Huntingtin (HTT, HD) and Ataxin 1 (ATXN1, SCA1), have unique functions and biological properties. Here, we review HD and SCA1 with a focus on how their disease-specific and shared features may provide informative insights.

Keywords: Huntington’s disease; polyglutamine neurodegenerative disease; spinocerebellar ataxia type 1.

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxin-1 / genetics
  • Genetic Association Studies
  • Humans
  • Huntington Disease* / genetics
  • Nervous System Diseases* / genetics
  • Proteins / genetics
  • Spinocerebellar Ataxias* / genetics
  • Trinucleotide Repeat Expansion / genetics
  • Trinucleotide Repeats

Substances

  • Ataxin-1
  • Proteins