Cross-talking noncoding RNAs contribute to cell-specific neurodegeneration in SCA7

Jennifer Y Tan, Keith W Vance, Miguel A Varela, Tamara Sirey, Lauren M Watson, Helen J Curtis, Martina Marinello, Sandro Alves, Bruno R Steinkraus, Sarah Cooper, Tatyana Nesterova, Neil Brockdorff, Tudor A Fulga, Alexis Brice, Annie Sittler, Peter L Oliver, Matthew J Wood, Chris P Ponting, Ana C Marques

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

Abstract

What causes the tissue-specific pathology of diseases resulting from mutations in housekeeping genes? Specifically, in spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disorder caused by a CAG-repeat expansion in ATXN7 (which encodes an essential component of the mammalian transcription coactivation complex, STAGA), the factors underlying the characteristic progressive cerebellar and retinal degeneration in patients were unknown. We found that STAGA is required for the transcription initiation of miR-124, which in turn mediates the post-transcriptional cross-talk between lnc-SCA7, a conserved long noncoding RNA, and ATXN7 mRNA. In SCA7, mutations in ATXN7 disrupt these regulatory interactions and result in a neuron-specific increase in ATXN7 expression. Strikingly, in mice this increase is most prominent in the SCA7 disease-relevant tissues, namely the retina and cerebellum. Our results illustrate how noncoding RNA-mediated feedback regulation of a ubiquitously expressed housekeeping gene may contribute to specific neurodegeneration.

Original languageEnglish
Pages (from-to)955-961
Number of pages7
JournalNature Structural and Molecular Biology
Volume21
Issue number11
Early online date12 Oct 2014
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • Animals
  • Cell Line, Tumor
  • Cerebellum
  • Feedback, Physiological
  • Female
  • Fibroblasts
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Male
  • Mice
  • MicroRNAs
  • Mutation
  • Nerve Tissue Proteins
  • Neurons
  • RNA, Long Noncoding
  • RNA, Messenger
  • Retina
  • Signal Transduction
  • Spinocerebellar Ataxias
  • Transcription Initiation, Genetic

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