TY - JOUR
T1 - Mechanisms of DJ-1 neuroprotection in a cellular model of Parkinson's disease
AU - Liu, Fang
AU - Nguyen, Jamie L.
AU - Hulleman, John D.
AU - Li, Li
AU - Rochet, Jean Christophe
PY - 2008/6
Y1 - 2008/6
N2 - 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.
AB - 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.
KW - DJ-1
KW - GSH
KW - Hsp70
KW - Proteasome dysfunction
KW - Rotenone
KW - Synuclein
UR - http://www.scopus.com/inward/record.url?scp=44649174333&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44649174333&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2008.05333.x
DO - 10.1111/j.1471-4159.2008.05333.x
M3 - Article
C2 - 18331584
AN - SCOPUS:44649174333
SN - 0022-3042
VL - 105
SP - 2435
EP - 2453
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 6
ER -