Molecular chaperone-mediated rescue of mitophagy by a Parkin RING1 domain mutant.
Mitochondrial dysfunction is characteristic of many neurodegenerative diseases. The Parkinson's disease-associated ubiquitin-protein ligase, Parkin, is important in the elimination of damaged mitochondria by autophagy (mitophagy) in a multistep process. Here, we show that a Parkin RING domain mutant (C289G) fails to redistribute to damaged mitochondria and cannot induce mitophagy after treatment with the mitochondrial uncoupler carbonyl cyanide m-methylhydrazone, because of protein misfolding and aggregation. Parkin(C289G) aggregation and inclusion formation were suppressed by the neuronal DnaJ/Hsp40 chaperone HSJ1a(DNAJB2a). Importantly, HSJ1a and DNAJB6 also restored mitophagy by promoting the relocation of Parkin(C289G) and the autophagy marker LC3 to depolarized mitochondria. The rescue of Parkin activity and suppression of aggregation were J domain dependent for HSJ1a, suggesting the involvement of Hsp70 in these processes, but were not dependent on the HSJ1a ubiquitin interaction motif. HSJ1a expression did not enhance mitophagy mediated by wild-type Parkin. These data show the potential of molecular chaperones to mediate the functional recovery of Parkin misfolding mutants and to combat deficits associated with Parkin aggregation in Parkinson's disease.
Rose
Johanna M
JM
UCL Institute of Ophthalmology, London, UK.
Novoselov
Sergey S
SS
Robinson
Philip A
PA
Cheetham
Michael E
ME
D001343:Autophagy; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000201:enzymology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
C121958:DNAJB2 protein, human; D050956:HSP40 Heat-Shock Proteins; D018832:Molecular Chaperones; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein