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Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration

Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration
Hwang, JY[Hwang, J-Y]Lee, J[Lee, J.]Oh, CK[Oh, C-K]Kang, HW[Kang, H. W.]Hwang, IY[Hwang, I-Y]Um, JW[Um, J. W.]Park, HC[Park, H. C.]Kim, S[Kim, S.]Shin, JH[Shin, J-H]Park, WY[Park, W-Y]Darnell, RB[Darnell, R. B.]Um, HD[Um, H-D]Chung, KC[Chung, K. C.]Kim, K[Kim, K.]Oh, YJ[Oh, Y. J.]
DGIST Authors
Kim, K[Kim, K.]
Issue Date
Cell Death and Disease, 7
Article Type
1 Methyl 4 PhenylpyridiniumAdultAnimal CellAnimal TissueAutopsyBenzyloxycarbonylleucylleucylleucinalBrain ProteinCalcium Binding ProteinCalpainCalpeptinCerebellar Degeneration Related Protein 2Controlled StudyCorpus StriatumCytotoxicityDegenerative DiseaseDopaminergic Nerve CellExperimental ParkinsonismFemaleGene OverexpressionHumanHuman TissueMesencephalonMessenger RNANerve Cell CultureNeuropathologyNon-HumanOncoproteinPrimary Cell CulturePriority JournalProteasomeProtein DegradationProtein ExpressionProtein FunctionRatSignal TransductionTyrosine3 MonooxygenaseUbiquitinUnclassified Drug
Cerebellar degeneration-related protein 2 (cdr2) is expressed in the central nervous system, and its ectopic expression in tumor cells of patients with gynecological malignancies elicits immune responses by cdr2-specific autoantibodies and T lymphocytes, leading to neurological symptoms. However, little is known about the regulation and function of cdr2 in neurodegenerative diseases. Because we found that cdr2 is highly expressed in the midbrain, we investigated the role of cdr2 in experimental models of Parkinson's disease (PD). We found that cdr2 levels were significantly reduced after stereotaxic injection of 1-methyl-4-phenylpyridinium (MPP+) into the striatum. cdr2 levels were also decreased in the brains of post-mortem PD patients. Using primary cultures of mesencephalic neurons and MN9D cells, we confirmed that MPP + reduces cdr2 in tyrosine hydroxylase-positive dopaminergic neuronal cells. The MPP+-induced decrease of cdr2 was primarily caused by calpain-and ubiquitin proteasome system-mediated degradation, and cotreatment with pharmacological inhibitors of these enzymes or overexpression of calcium-binding protein rendered cells less vulnerable to MPP+-mediated cytotoxicity. Consequently, overexpression of cdr2 rescued cells from MPP+-induced cytotoxicity, whereas knockdown of cdr2 accelerated toxicity. Collectively, our findings provide insights into the novel regulatory mechanism and potentially protective role of onconeural protein during dopaminergic neurodegeneration. © 2016 Macmillan Publishers Limited All rights reserved.
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Brain and Cognitive SciencesETC1. Journal Articles

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