The ataxia (axJ) mutation causes abnormal GABAA receptor turnover in mice

PLoS Genet. 2009 Sep;5(9):e1000631. doi: 10.1371/journal.pgen.1000631. Epub 2009 Sep 4.

Abstract

Ataxia represents a pathological coordination failure that often involves functional disturbances in cerebellar circuits. Purkinje cells (PCs) characterize the only output neurons of the cerebellar cortex and critically participate in regulating motor coordination. Although different genetic mutations are known that cause ataxia, little is known about the underlying cellular mechanisms. Here we show that a mutated ax(J) gene locus, encoding the ubiquitin-specific protease 14 (Usp14), negatively influences synaptic receptor turnover. Ax(J) mouse mutants, characterized by cerebellar ataxia, display both increased GABA(A) receptor (GABA(A)R) levels at PC surface membranes accompanied by enlarged IPSCs. Accordingly, we identify physical interaction of Usp14 and the GABA(A)R alpha1 subunit. Although other currently unknown changes might be involved, our data show that ubiquitin-dependent GABA(A)R turnover at cerebellar synapses contributes to ax(J)-mediated behavioural impairment.

Publication types

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

MeSH terms

  • Animals
  • Ataxia / genetics*
  • Ataxia / metabolism*
  • Cell Line
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Expression
  • Humans
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Protein Binding
  • Purkinje Cells / metabolism
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / metabolism

Substances

  • Receptors, GABA-A
  • Usp14 protein, mouse
  • Ubiquitin Thiolesterase