Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells

Hum Mol Genet. 2015 Jan 1;24(1):100-17. doi: 10.1093/hmg/ddu422. Epub 2014 Aug 20.


The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado-Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of α5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Cell Differentiation
  • Cells, Cultured
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / metabolism
  • HEK293 Cells
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Integrin alpha5 / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism*
  • PC12 Cells
  • Peptides / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Rats
  • Rats, Wistar
  • Repressor Proteins / metabolism*
  • Transcription Factors / metabolism*


  • Integrin alpha5
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • Repressor Proteins
  • Transcription Factors
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3
  • Atxn3 protein, mouse
  • Atxn3 protein, rat
  • Proteasome Endopeptidase Complex