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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Polyglutamine expanded Ataxin-7 induces DNA damage and alters FUS localization and function.

Frida Niss1, Wajiha Zaidi1, Einar Hallberg1

  • 1Stockholm University, Department of Biochemistry and Biophysics, Svante Arrhenius väg 16C, 10691 Stockholm, Sweden.

Molecular and Cellular Neurosciences
|December 18, 2020
PubMed
Summary
This summary is machine-generated.

Polyglutamine diseases like Spinocerebellar ataxia type 7 (SCA7) involve FUS protein sequestration and altered RNA regulation. This study reveals increased DNA damage in SCA7 cells, suggesting a role in neuronal dysfunction.

Keywords:
FUSNeurodegenerationPolyglutamine diseaseRNA-binding protein

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Polyglutamine (polyQ) diseases, including Spinocerebellar ataxia type 7 (SCA7), are linked to expanded polyQ repeats in proteins.
  • Protein aggregation and sequestration of essential cellular components are proposed mechanisms in polyQ disorders.
  • The RNA-binding protein FUS is found in polyQ aggregates, but its specific role in SCA7 pathogenesis is not well understood.

Purpose of the Study:

  • To investigate the localization and function of the FUS protein in a cellular model of Spinocerebellar ataxia type 7 (SCA7).
  • To determine if FUS sequestration affects its RNA regulatory functions and contributes to neuronal dysfunction in SCA7.
  • To assess the extent of DNA damage in SCA7 models and patient cells.

Main Methods:

  • Utilized a stable inducible PC12 cell model expressing the SCA7 polyQ protein ATXN7.
  • Analyzed FUS localization and expression of FUS-regulated mRNAs.
  • Assessed the formation of DNA damage foci (γH2AX) and DNA strand breaks using comet assays.
  • Examined DNA damage in SCA7 patient-derived fibroblasts.

Main Results:

  • Significant sequestration of FUS protein was observed, correlating with increased cytoplasmic localization.
  • Reduced expression of FUS-regulated messenger RNAs (mRNAs) was detected in mutant ATXN7 cells.
  • While FUS's role in γH2AX foci formation remained unchanged, mutant ATXN7 cells showed a statistical increase in γH2AX foci and DNA strand breaks.
  • SCA7 patient fibroblasts exhibited a trend towards increased DNA damage.

Conclusions:

  • FUS sequestration and subsequent disruption of its RNA regulatory functions may contribute to SCA7 pathology.
  • Increased DNA damage, evidenced by γH2AX foci and strand breaks, is a significant feature in SCA7 models and patients.
  • Combined alterations in FUS function and DNA damage pathways likely play a role in the neurodegenerative mechanisms of SCA7.