Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation

Kang Woo Lee, Xin Zhao, Joo Young Im, Hilary Grosso, Won Hee Jang, Teresa W. Chan, Patricia K. Sonsalla, Dwight C. German, Hidenori Ichijo, Eunsung Junn, M. Maral Mouradian

Research output: Contribution to journalArticle

43 Citations (Scopus)

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 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.

Original languageEnglish (US)
Article numbere29935
JournalPLoS One
Volume7
Issue number1
DOIs
StatePublished - Jan 10 2012

Fingerprint

MAP Kinase Kinase Kinase 5
neuroglia
Neuroglia
Toxicity
phosphotransferases (kinases)
apoptosis
Chemical activation
toxicity
Dopaminergic Neurons
Dopamine
Neurons
dopamine
Parkinson Disease
Oxidative stress
Parkinson disease
Oxidative Stress
neurons
mice
Corpus Striatum
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lee, K. W., Zhao, X., Im, J. Y., Grosso, H., Jang, W. H., Chan, T. W., ... Mouradian, M. M. (2012). Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS One, 7(1), [e29935]. https://doi.org/10.1371/journal.pone.0029935

Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. / 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. Maral.

In: PLoS One, Vol. 7, No. 1, e29935, 10.01.2012.

Research output: Contribution to journalArticle

Lee, KW, Zhao, X, Im, JY, Grosso, H, Jang, WH, Chan, TW, Sonsalla, PK, German, DC, Ichijo, H, Junn, E & Mouradian, MM 2012, 'Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation', PLoS One, vol. 7, no. 1, e29935. https://doi.org/10.1371/journal.pone.0029935
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. Maral. / Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. In: PLoS One. 2012 ; Vol. 7, No. 1.
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