BAG1 restores formation of functional DJ-1 L166P dimers and DJ-1 chaperone activity.
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.
Deeg
Sebastian
S
Department for Neurology, Georg-August University Göttingen, 37073 Göttingen, Germany.
Gralle
Mathias
M
Sroka
Kamila
K
Bähr
Mathias
M
Wouters
Fred Silvester
FS
Kermer
Pawel
P
D019943:Amino Acid Substitution / Q000235:genetics*; D016923:Cell Death; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D055503:Protein Multimerization; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
C091732:BCL2-associated athanogene 1 protein; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D050505:Mutant Proteins; D015513:Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1