The Homocysteine-inducible Endoplasmic Reticulum Stress Protein Counteracts Calcium Store Depletion and Induction of CCAAT Enhancer-binding Protein Homologous Protein in a Neurotoxin Model of Parkinson Disease

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 up-regulation, 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.