Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1

Nat Genet. 1998 Jun;19(2):148-54. doi: 10.1038/502.

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in ataxin-1. In affected neurons of SCA1 patients and transgenic mice, mutant ataxin-1 accumulates in a single, ubiquitin-positive nuclear inclusion. In this study, we show that these inclusions stain positively for the 20S proteasome and the molecular chaperone HDJ-2/HSDJ. Similarly, HeLa cells transfected with mutant ataxin-1 develop nuclear aggregates which colocalize with the 20S proteasome and endogenous HDJ-2/HSDJ. Overexpression of wild-type HDJ-2/HSDJ in HeLa cells decreases the frequency of ataxin-1 aggregation. These data suggest that protein misfolding is responsible for the nuclear aggregates seen in SCA1, and that overexpression of a DnaJ chaperone promotes the recognition of a misfolded polyglutamine repeat protein, allowing its refolding and/or ubiquitin-dependent degradation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ataxin-1
  • Ataxins
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Cysteine Endopeptidases / metabolism*
  • HSC70 Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Chaperones / physiology*
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proteasome Endopeptidase Complex
  • Protein Conformation
  • Protein Folding*
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Spinocerebellar Degenerations / genetics
  • Spinocerebellar Degenerations / pathology*
  • Transfection

Substances

  • ATXN1 protein, human
  • Ataxin-1
  • Ataxins
  • Atxn1 protein, mouse
  • Carrier Proteins
  • DNAJA1 protein, human
  • HSC70 Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • HSPA8 protein, human
  • Heat-Shock Proteins
  • Hspa8 protein, mouse
  • Molecular Chaperones
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex