Gcn5 loss-of-function accelerates cerebellar and retinal degeneration in a SCA7 mouse model

Hum Mol Genet. 2012 Jan 15;21(2):394-405. doi: 10.1093/hmg/ddr474. Epub 2011 Oct 14.

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by expansion of a CAG repeat encoding a polyglutamine tract in ATXN7, a component of the SAGA histone acetyltransferase (HAT) complex. Previous studies provided conflicting evidence regarding the effects of polyQ-ATXN7 on the activity of Gcn5, the HAT catalytic subunit of SAGA. Here, we report that reducing Gcn5 expression accelerates both cerebellar and retinal degeneration in a mouse model of SCA7. Deletion of Gcn5 in Purkinje cells in mice expressing wild-type (wt) Atxn7, however, causes only mild ataxia and does not lead to the early lethality observed in SCA7 mice. Reduced Gcn5 expression strongly enhances retinopathy in SCA7 mice, but does not affect the known transcriptional targets of Atxn7, as expression of these genes is not further altered by Gcn5 depletion. These findings demonstrate that loss of Gcn5 functions can contribute to the time of onset and severity of SCA7 phenotypes, and suggest that non-transcriptional functions of SAGA may play a role in neurodegeneration in this disease.

Publication types

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

MeSH terms

  • Animals
  • Ataxin-7
  • Base Sequence
  • Cerebellum / pathology*
  • DNA Primers
  • Gene Deletion
  • Mice
  • Nerve Tissue Proteins / genetics*
  • Polymerase Chain Reaction
  • Retinal Degeneration / genetics*
  • Trinucleotide Repeats
  • p300-CBP Transcription Factors / genetics*

Substances

  • Ataxin-7
  • Atxn7 protein, mouse
  • DNA Primers
  • Nerve Tissue Proteins
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor