Apoptosis Signal-Regulating Kinase 1 Mediates MPTP Toxicity and Regulates Glial Activation

作者：Lee Kang Woo^*; Zhao Xin; Im Joo Young; Grosso Hilary; Jang Won Hee; Chan Teresa W; Sonsalla Patricia K; German Dwight C; Ichijo Hidenori; Junn Eunsung; Mouradian M Mara

来源：PLos One, 2012, 7(1): 242-249.

DOI：10.1371/journal.pone.0029935

Apoptosis signal-regulating kinase 1 ASIK1) member of the mitogen-activated protein kinase 3 family, is activated by oxidative stress. The death-signaling pathway mediated by ASK1 is inhibited by DJ 1, which is linked to recessively inherited Parkinson%26apos;s disease (PD). Considering that DJ-1 deficiency exacerbates the toxicity of the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we sought to investigate the direct role and mechanism of ASK1 in MPTP-induced dopamine neuron toxicity. In the present study, we found that MPTP administration to wild-type mice activates ASK1 in the midbrain. In ASK1 null mice, MPTP-induced motor impairment was less profound, and striatal dopamine content and nigral dopamine neuron counts were relatively preserved compared to wild type littermates. Further, microglia and astrocyte activation seen in wild-type mice challenged with MPTP was markedly attenuated in,ASK1(-/-) mice. These data suggest that ASK1 is a key player in MPTP-induced glial activation linking oxidative stress with neuroinflammation, two well recognized pathogenetic factors in PD. These findings demonstrate that ASK1 is an important effector of MPTP-induced toxicity and suggest that inhibiting this kinase is a plausible therapeutic strategy for protecting dopamine neurons in PD.

• 出版日期2012-1-10