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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

Kyota Fujita1, Yoko Nakamura1, Tsutomu Oka1

  • 1Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Nature Communications
|May 9, 2013
PubMed

Insights

A common mechanism links neurodegenerative diseases: transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97

Area of Science:

  • Neurobiology
  • Molecular Biology
  • Genetics

Background:

  • Multiple neurodegenerative disorders may share a common underlying mechanism.
  • Polyglutamine diseases are a class of neurodegenerative disorders characterized by the expansion of polyglutamine tracts in specific proteins.

Purpose of the Study:

  • To investigate the potential common pathomechanism linking multiple polyglutamine diseases.
  • To elucidate the role of transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 in the pathology of these diseases.

Main Methods:

  • Investigated the direct binding of TERA/VCP/p97 to polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7, androgen receptor).
  • Assessed the effect of normal and mutant polyglutamine proteins on TERA/VCP/p97 dynamism.
  • Examined the role of TERA/VCP/p97 in DNA double-stranded break repair in neuronal cells.
  • Utilized polyglutamine disease fly models to assess the therapeutic potential of TERA/VCP/p97.

Main Results:

  • TERA/VCP/p97 directly binds to polyglutamine proteins via the polyglutamine sequence.
  • Mutant polyglutamine proteins, but not normal ones, affect TERA/VCP/p97 dynamism.
  • TERA/VCP/p97's DNA double-stranded break repair function is critical for neuronal pathology in these diseases.
  • Mutant polyglutamine proteins impair TERA/VCP/p97 accumulation and DNA repair, leading to unrepaired double-stranded breaks.
  • TERA/VCP/p97 intervention improved double-stranded break repair and extended lifespan in fly models.

Conclusions:

  • A novel common pathomechanism in multiple polyglutamine diseases involves the DNA repair function of TERA/VCP/p97.
  • TERA/VCP/p97 is a potential therapeutic target for polyglutamine diseases.

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