Misfolding of proteins with a polyglutamine expansion is facilitated by proteasomal chaperones

J Biol Chem. 2009 Jan 16;284(3):1917-29. doi: 10.1074/jbc.M806256200. Epub 2008 Nov 5.


Deposition of misfolded proteins with a polyglutamine expansion is a hallmark of Huntington disease and other neurodegenerative disorders. Impairment of the proteolytic function of the proteasome has been reported to be both a cause and a consequence of polyglutamine accumulation. Here we found that the proteasomal chaperones that unfold proteins to be degraded by the proteasome but also have non-proteolytic functions co-localized with huntingtin inclusions both in primary neurons and in Huntington disease patients and formed a complex independently of the proteolytic particle. Overexpression of Rpt4 or Rpt6 facilitated aggregation of mutant huntingtin and ataxin-3 without affecting proteasomal degradation. Conversely, reducing Rpt6 or Rpt4 levels decreased the number of inclusions in primary neurons, indicating that endogenous Rpt4 and Rpt6 facilitate inclusion formation. In vitro reconstitution experiments revealed that purified 19S particles promote mutant huntingtin aggregation. When fused to the ornithine decarboxylase destabilizing sequence, proteins with expanded polyglutamine were efficiently degraded and did not aggregate. We propose that aggregation of proteins with expanded polyglutamine is not a consequence of a proteolytic failure of the 20S proteasome. Rather, aggregation is elicited by chaperone subunits of the 19S particle independently of proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • HeLa Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / immunology*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism*
  • Ornithine Decarboxylase / genetics
  • Ornithine Decarboxylase / metabolism
  • Polyglutamic Acid / genetics
  • Polyglutamic Acid / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Folding*
  • Rats
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*


  • HTT protein, human
  • Htt protein, rat
  • Huntingtin Protein
  • Molecular Chaperones
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Polyglutamic Acid
  • ATXN3 protein, human
  • Ataxin-3
  • Proteasome Endopeptidase Complex
  • 26S proteasome non-ATPase regulatory subunit 13
  • Ornithine Decarboxylase