Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease.
Mitochondrial dysfunction, proteasome inhibition, and alpha-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 alpha-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 alpha-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 alpha-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.
Liu
Fang
F
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-2091, USA.
Nguyen
Jamie L
JL
Hulleman
John D
JD
Li
Li
L
Rochet
Jean-Christophe
JC
D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015513:Oncogene Proteins / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism* / Q000517:prevention & control*; D011247:Pregnancy; D000071617:Protein Deglycase DJ-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000037:antagonists & inhibitors / Q000633:toxicity
D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D015513:Oncogene Proteins; D012402:Rotenone; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1