Nuclear accumulation of stress response mRNAs contributes to the neurodegeneration caused by Fragile X premutation rCGG repeats

PLoS Genet. 2011 Jun;7(6):e1002102. doi: 10.1371/journal.pgen.1002102. Epub 2011 Jun 2.

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder seen in Fragile X premutation carriers. Previous studies found that Fragile X rCGG repeats are sufficient to cause neurodegeneration and that the rCGG repeat-binding proteins Pur α and hnRNP A2/B1 can modulate rCGG-mediated neuronal toxicity. To explore the role of Pur α in rCGG-mediated neurodegeneration further, we took a proteomic approach and identified more than 100 proteins that interact with Pur α. Of particular interest is Rm62, the Drosophila ortholog of p68 RNA helicase, which could modulate rCGG-mediated neurodegeneration. Here we show that rCGG repeats decreased the expression of Rm62 posttranscriptionally, leading to the nuclear accumulation of Hsp70 transcript, as well as additional mRNAs involved in stress and immune responses. Together these findings suggest that abnormal nuclear accumulation of these mRNAs, likely as a result of impaired nuclear export, could contribute to FXTAS pathogenesis.

Publication types

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

MeSH terms

  • Animals
  • Cell Nucleus / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila / genetics
  • Drosophila / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Fragile X Syndrome / genetics*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism
  • Mutation*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Neurons / metabolism*
  • RNA, Messenger / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • HSP70 Heat-Shock Proteins
  • Pur-alpha protein, Drosophila
  • RNA, Messenger
  • Transcription Factors
  • Fragile X Mental Retardation Protein