Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells

Cerebellum. 2014 Feb;13(1):29-41. doi: 10.1007/s12311-013-0516-5.


Spinocerebellar ataxia type 3 (SCA3) is caused by the abnormal expansion of CAG repeats within the ataxin-3 gene. Previously, we generated transgenic mice (SCA3 mice) that express a truncated form of ataxin-3 containing abnormally expanded CAG repeats specifically in cerebellar Purkinje cells (PCs). Here, we further characterize these SCA3 mice. Whole-cell patch-clamp analysis of PCs from advanced-stage SCA3 mice revealed a significant decrease in membrane capacitance due to poor dendritic arborization and the complete absence of metabotropic glutamate receptor subtype1 (mGluR1)-mediated retrograde suppression of synaptic transmission at parallel fiber terminals, with an overall preservation of AMPA receptor-mediated fast synaptic transmission. Because these cerebellar phenotypes are reminiscent of retinoic acid receptor-related orphan receptor α (RORα)-defective staggerer mice, we examined the levels of RORα in the SCA3 mouse cerebellum by immunohistochemistry and found a marked reduction of RORα in the nuclei of SCA3 mouse PCs. To confirm that the defects in SCA3 mice were caused by postnatal deposition of mutant ataxin-3 in PCs, not by genome disruption via transgene insertion, we tried to reduce the accumulation of mutant ataxin-3 in developing PCs by viral vector-mediated expression of CRAG, a molecule that facilitates the degradation of stress proteins. Concomitant with the removal of mutant ataxin-3, CRAG-expressing PCs had greater numbers of differentiated dendrites compared to non-transduced PCs and exhibited retrograde suppression of synaptic transmission following mGluR1 activation. These results suggest that postnatal nuclear accumulation of mutant ataxin-3 disrupts dendritic differentiation and mGluR-signaling in SCA3 mouse PCs, and this disruption may be caused by a defect in a RORα-driven transcription pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Ataxin-3
  • Cell Nucleus / physiology
  • Cerebellum / growth & development
  • Cerebellum / physiology*
  • Dendrites / pathology
  • Dendrites / physiology*
  • Electric Capacitance
  • In Vitro Techniques
  • Machado-Joseph Disease / genetics
  • Machado-Joseph Disease / pathology
  • Machado-Joseph Disease / physiopathology
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Peptides
  • Purkinje Cells / pathology
  • Purkinje Cells / physiology*
  • Receptors, AMPA / metabolism
  • Receptors, Metabotropic Glutamate / metabolism*
  • Synaptic Transmission
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Nuclear Proteins
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Peptides
  • Receptors, AMPA
  • Receptors, Metabotropic Glutamate
  • Transcription Factors
  • metabotropic glutamate receptor type 1
  • polyglutamine
  • Ataxin-3
  • Atxn3 protein, mouse