title: 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.
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 up-regulation, 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.
authors.affiliation: Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32816, USA.
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chigurupati
authors.forename: Zelan
authors.initials: Z
authors.lastname: Wei
authors.forename: Cherine
authors.initials: C
authors.lastname: Belal
authors.forename: Myriam
authors.initials: M
authors.lastname: Vandermey
authors.forename: George A
authors.initials: GA
authors.lastname: Kyriazis
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.forename: Sic L
authors.initials: SL
authors.lastname: Chan
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D016716:PC12 Cells; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D013312:Stress, Physiological / Q000502:physiology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C497249:DDIT3 protein, human; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D025801:Ubiquitin; D051742:Transcription Factor CHOP; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium