Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex

EMBO J. 2018 Jan 17;37(2):282-299. doi: 10.15252/embj.201797212. Epub 2017 Dec 6.

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin gene (HTT). Molecular chaperones have been implicated in suppressing or delaying the aggregation of mutant Htt. Using in vitro and in vivo assays, we have identified a trimeric chaperone complex (Hsc70, Hsp110, and J-protein) that completely suppresses fibrilization of HttExon1Q48 The composition of this chaperone complex is variable as recruitment of different chaperone family members forms distinct functional complexes. The trimeric chaperone complex is also able to resolubilize Htt fibrils. We confirmed the biological significance of these findings in HD patient-derived neural cells and on an organismal level in Caenorhabditis elegans Among the proteins in this chaperone complex, the J-protein is the concentration-limiting factor. The single overexpression of DNAJB1 in HEK293T cells is sufficient to profoundly reduce HttExon1Q97 aggregation and represents a target of future therapeutic avenues for HD.

Keywords: HttpolyQ; NPCs; disaggregation; molecular chaperones; suppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • HEK293 Cells
  • HSC70 Heat-Shock Proteins* / chemistry
  • HSC70 Heat-Shock Proteins* / genetics
  • HSC70 Heat-Shock Proteins* / metabolism
  • HSP110 Heat-Shock Proteins* / chemistry
  • HSP110 Heat-Shock Proteins* / genetics
  • HSP110 Heat-Shock Proteins* / metabolism
  • HSP40 Heat-Shock Proteins* / chemistry
  • HSP40 Heat-Shock Proteins* / genetics
  • HSP40 Heat-Shock Proteins* / metabolism
  • Humans
  • Huntingtin Protein* / chemistry
  • Huntingtin Protein* / genetics
  • Huntingtin Protein* / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology
  • Multiprotein Complexes* / chemistry
  • Multiprotein Complexes* / genetics
  • Multiprotein Complexes* / metabolism
  • Neurons / metabolism*
  • Neurons / pathology
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / metabolism
  • Protein Aggregation, Pathological / pathology

Substances

  • DNAJB1 protein, human
  • HSC70 Heat-Shock Proteins
  • HSP110 Heat-Shock Proteins
  • HSP40 Heat-Shock Proteins
  • HSPA8 protein, human
  • HSPH1 protein, human
  • HTT protein, human
  • Huntingtin Protein
  • Multiprotein Complexes