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

Nat Commun. 2013;4:1816. doi: 10.1038/ncomms2828.

Abstract

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.

Publication types

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

MeSH terms

  • Adenosine Triphosphatases / deficiency*
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Animals, Genetically Modified
  • Ataxin-1
  • Ataxins
  • Cell Cycle Proteins / deficiency*
  • Cell Cycle Proteins / metabolism
  • Cerebral Cortex / pathology
  • DNA Breaks, Double-Stranded
  • DNA Repair*
  • Drosophila melanogaster / metabolism
  • Endoplasmic Reticulum / metabolism
  • Green Fluorescent Proteins / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Immunoprecipitation
  • Inclusion Bodies / metabolism
  • Longevity
  • Mice
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Mutant Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Peptides / metabolism*
  • Phenotype
  • Protein Binding
  • Protein Transport
  • Valosin Containing Protein

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Cell Cycle Proteins
  • Histones
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • polyglutamine
  • Adenosine Triphosphatases
  • VCP protein, human
  • Valosin Containing Protein
  • Vcp protein, mouse