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 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.
Chigurupati
Srinivasulu
S
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida 32816, USA.
Wei
Zelan
Z
Belal
Cherine
C
Vandermey
Myriam
M
Kyriazis
George A
GA
Arumugam
Thiruma V
TV
Chan
Sic L
SL
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
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