Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease

Fang Liu, Jamie L. Nguyen, John D. Hulleman, Li Li, Jean Christophe Rochet

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

Mitochondrial dysfunction, proteasome inhibition, and α-synuclein aggregation are thought to play important roles in the pathogenesis of Parkinson's disease (PD). Rare cases of early-onset PD have been linked to mutations in the gene encoding DJ-1, a protein with antioxidant and chaperone functions. In this study, we examined whether DJ-1 protects against various stresses involved in PD, and we investigated the underlying mechanisms. Expression of wild-type DJ-1 rescued primary dopaminergic neurons from toxicity elicited by rotenone, proteasome inhibitors, and mutant α-synuclein. Neurons with reduced levels of endogenous DJ-1 were sensitized to each of these insults, and DJ-1 mutants involved in familial PD exhibited decreased neuroprotective activity. DJ-1 alleviated rotenone toxicity by up-regulating total intracellular glutathione. In contrast, inhibition of α-synuclein toxicity by DJ-1 correlated with up-regulation of the stress-inducible form of Hsp70. RNA interference studies revealed that this increase in Hsp70 levels was necessary for DJ-1-mediated suppression of α-synuclein aggregation, but not toxicity. Our findings suggest that DJ-1 acts as a versatile pro-survival factor in dopaminergic neurons, activating different protective mechanisms in response to a diverse range of PD-related insults.

Original languageEnglish (US)
Pages (from-to)2435-2453
Number of pages19
JournalJournal of Neurochemistry
Volume105
Issue number6
DOIs
StatePublished - Jun 1 2008

Keywords

  • DJ-1
  • GSH
  • Hsp70
  • Proteasome dysfunction
  • Rotenone
  • Synuclein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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