Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 27, Pages 18323-18333Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.020891
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- American Federation on Aging Research
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The endoplasmic reticulum (ER) is a key organelle regulating intracellular Ca2+ homeostasis. Oxidants and mitochondria-derived free radicals can target ER-based Ca2+ regulatory proteins and cause uncontrolled Ca2+ release that may contribute to protracted ER stress and apoptosis. Several ER stress proteins have been suggested to counteract the deregulation of ER Ca2+ 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 Ca2+ depletion. Conversely, Herp overexpression confers protection by blocking 1-methyl-4-phenylpyridinium-induced CHOP upregulation, ER Ca2+ store depletion, and mitochondrial Ca2+ 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 Ca2+ homeostasis. Thus, elucidating the underlying molecular mechanism(s) whereby Herp counteracts Ca2+ 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.
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