BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity

J Cell Biol. 2010 Feb 22;188(4):505-13. doi: 10.1083/jcb.200904103. Epub 2010 Feb 15.

Abstract

Mutations in the gene coding for DJ-1 protein lead to early-onset recessive forms of Parkinson's disease. It is believed that loss of DJ-1 function is causative for disease, although the function of DJ-1 still remains a matter of controversy. We show that DJ-1 is localized in the cytosol and is associated with membranes and organelles in the form of homodimers. The disease-related mutation L166P shifts its subcellular distribution to the nucleus and decreases its ability to dimerize, impairing cell survival. Using an intracellular foldase biosensor, we found that wild-type DJ-1 possesses chaperone activity, which is abolished by the L166P mutation. We observed that this aberrant phenotype can be reversed by the expression of the cochaperone BAG1 (Bcl-2-associated athanogene 1), restoring DJ-1 subcellular distribution, dimer formation, and chaperone activity and ameliorating cell survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Cell Death
  • Cell Line
  • DNA-Binding Proteins / metabolism*
  • Humans
  • Immunoprecipitation
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Molecular Chaperones / metabolism*
  • Mutant Proteins / metabolism*
  • Oncogene Proteins / metabolism*
  • Protein Binding
  • Protein Deglycase DJ-1
  • Protein Multimerization*
  • Protein Transport
  • Recombinant Proteins / metabolism
  • Subcellular Fractions / metabolism
  • Transcription Factors / metabolism*

Substances

  • BCL2-associated athanogene 1 protein
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Mutant Proteins
  • Oncogene Proteins
  • Recombinant Proteins
  • Transcription Factors
  • PARK7 protein, human
  • Protein Deglycase DJ-1