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Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration

Authors
 J-Y Hwang  ;  J Lee  ;  C-K Oh  ;  H W Kang  ;  I-Y Hwang  ;  J W Um  ;  H C Park  ;  S Kim  ;  J-H Shin  ;  W-Y Park  ;  R B Darnell  ;  H-D Um  ;  K C Chung  ;  K Kim  ;  Y J Oh 
Citation
 CELL DEATH & DISEASE, Vol.7(6) : 2240, 2016 
Journal Title
 CELL DEATH & DISEASE 
Issue Date
2016
MeSH
1-Methyl-4-phenylpyridinium ; Aging/metabolism ; Animals ; Calpain/metabolism ; Cell Death ; Cell Line ; Disease Models, Animal ; Dopaminergic Neurons/metabolism ; Down-Regulation ; Mesencephalon/metabolism ; Nerve Degeneration/metabolism* ; Nerve Degeneration/pathology* ; Nerve Tissue Proteins/metabolism* ; Neuroprotection ; Parkinson Disease/metabolism ; Parkinson Disease/pathology ; Postmortem Changes ; Proteolysis* ; Rats, Sprague-Dawley ; Substantia Nigra/metabolism ; Substantia Nigra/pathology ; Tyrosine 3-Monooxygenase/metabolism ; Ubiquitin/metabolism
Abstract
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.
DOI
10.1038/cddis.2016.151
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Um, Ji Won(엄지원)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/151643
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