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

Author

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

Subjects
APOPTOSIS, KINASES, MITOGEN-activated protein kinases, OXIDATIVE stress, PARKINSON'S disease, DOPAMINERGIC neurons
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 ASK12/2 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. [ABSTRACT FROM AUTHOR]

Published
2012
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89. CalbindinD28Kin the nucleus of nerve growth factortreated PC12 cells

Author

McMahon, Anne, Lephart, Edwin D., Chi, Susan, Lee, Michael, lacopino, Anthony M., and German, Dwight C.

Abstract

CALBINDIN-D28K(CB) is a calcium-binding protein found within a subset of neurons, which has been proposed to buffer intracellular calcium and to protect cells from calcium-induced neurodegeneration. The rat pheochromocytoma PC12 cell line has been an invaluable tool for studying neuronal development and characterizing the molecular actions of nerve growth factor (NGF). Using Western and RNAse protection analyses and immunocytochemical and cell fractionation techniques, we now report that NGF induces the expression of CB not only in the cytoplasm and neurites, but also within the nuclei of PC12 cells. These data indicate that PC12 cells can serve as a useful model system in which to study the functions of CB and the role of nuclear CB.

Published
1996

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