Prefoldin Prevents Aggregation of α-synuclein

Brain Res. 2014 Jan 13;1542:186-94.

Abstract

Protein aggregation is observed in various neurodegeneration diseases, including Parkinson's disease (PD). Alpha-synuclein, a causative gene product of familial PD, is a major component of large aggregates (inclusion bodies) in PD. Prefoldin, a molecular chaperone comprised of six subunits, PFD1~6, prevents misfolding of newly synthesized nascent polypeptides and also prevents aggregation of protein such as a pathogenic form of Huntingtin, a causative gene product of Huntington disease. In this study, we first found that aggregation of TagRFP-tagged wild-type α-synuclein and its pathogenic mutants, but not that of GFP-tagged α-synuclein, occurred in transfected Neuro-2a cells. The fluorescence of GFP is weakened under the condition of pH 4.5-5.0, and TagRFP is a stable red fluorescence protein under an acidic condition. Aggregated TagRFP-wild-type α-synuclein and its pathogenic mutants in Neuro-2a cells were ubiquitinated and were colocalized with the prefoldin complex in the lysosome under this condition. Furthermore, knockdown of PFD2 and PFD5 disrupted prefoldin formation in α-synuclein-expressing cells, resulting in accumulation of aggregates of wild-type and pathogenic α-synuclein and in induction of cell death. The levels of aggregation and cell death in pathogenic α-synuclein-transfected cells tended to be higher than those in wild-type α-synuclein-transfected cells. These results suggest that prefoldin works as a protective factor in aggregated α-synuclein-induced cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Death / drug effects
  • Cell Death / genetics
  • Cell Line, Tumor
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation / genetics
  • Neuroblastoma / pathology
  • RNA, Small Interfering / pharmacology
  • Transfection
  • Ubiquitin / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*

Substances

  • Luminescent Proteins
  • Molecular Chaperones
  • RNA, Small Interfering
  • Ubiquitin
  • alpha-Synuclein
  • prefoldin
  • red fluorescent protein
  • Green Fluorescent Proteins