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Abbreviated Journal Title

J. Biol. Chem.

Keywords

Cell-Death; Oxidative Stress; Pc12 Cells; Permeability Transition; Sarcoplasmic-Reticulum; Dopaminergic-Neurons; Induced Apoptosis; Ca2+; Homeostasis; Er Stress; Herp; Biochemistry & Molecular Biology

Abstract

The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca(2+) homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca(2+) regulatory proteins and cause uncontrolled Ca(2+) release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca(2+) homeostasis and ER stress. Here we showed that knockdown of Herp, an ubiquitin-like domain containing ER stress protein, renders PC12 and MN9D cells vulnerable to 1-methyl-4-phenylpyridinium-induced cytotoxic cell death by a mechanism involving up-regulation of CHOP expression and ER Ca(2+) depletion. Conversely, Herp overexpression confers protection by blocking 1-methyl-4-phenylpyridinium-induced CHOP upregulation, ER Ca(2+) store depletion, and mitochondrial Ca(2+) accumulation in a manner dependent on a functional ubiquitin-proteasomal protein degradation pathway. Deletion of the ubiquitin-like domain of Herp or treatment with a proteasomal inhibitor abolished the central function of Herp in ER Ca(2+) homeostasis. Thus, elucidating the underlying molecular mechanism(s) whereby Herp counteracts Ca(2+) disturbances will provide insights into the molecular cascade of cell death in dopaminergic neurons and may uncover novel therapeutic strategies to prevent and ameliorate Parkinson disease progression.

Journal Title

Journal of Biological Chemistry

Volume

284

Issue/Number

27

Publication Date

1-1-2009

Document Type

Article

Language

English

First Page

18323

Last Page

18333

WOS Identifier

WOS:000267712400045

ISSN

0021-9258

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