title: Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation.
abstract: Apoptosis signal-regulating kinase 1 (ASK1), a 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'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 ASK⁻/⁻ 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.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America.
authors.forename: Kang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Joo-Young
authors.initials: JY
authors.lastname: Im
authors.forename: Hilary
authors.initials: H
authors.lastname: Grosso
authors.forename: Won Hee
authors.initials: WH
authors.lastname: Jang
authors.forename: Teresa W
authors.initials: TW
authors.lastname: Chan
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Sonsalla
authors.forename: Dwight C
authors.initials: DC
authors.lastname: German
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Eunsung
authors.initials: E
authors.lastname: Junn
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D059290:Dopaminergic Neurons / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000378:metabolism*; D020267:MPTP Poisoning / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009411:Nerve Endings / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000201:enzymology* / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
chemical_list: D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse