title: Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration.
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.
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.|Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: C-K
authors.initials: CK
authors.lastname: Oh
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Kang
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: I-Y
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: J W
authors.initials: JW
authors.lastname: Um
authors.affiliation: Graduate School of Medicine, Korea University, Ansan 425-707, Gyeonggi-do, Korea.
authors.forename: H C
authors.initials: HC
authors.lastname: Park
authors.affiliation: Graduate School of Medicine, Korea University, Ansan 425-707, Gyeonggi-do, Korea.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Gyeonggi-do, Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Gyeonggi-do, Korea.
authors.forename: W-Y
authors.initials: WY
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Darnell
authors.affiliation: Division of Radiation Cancer Biology, Korean Institute of Radiological & Medical Sciences, Seoul 01812, Korea.
authors.forename: H-D
authors.initials: HD
authors.lastname: Um
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: K C
authors.initials: KC
authors.lastname: Chung
authors.affiliation: Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 711-873, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Yonsei University College of Life Science and Biotechnology, Seoul 120-749, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Oh
mesh_terms: D015655:1-Methyl-4-phenylpyridinium; D000375:Aging / Q000378:metabolism; D000818:Animals; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism; D015536:Down-Regulation; D008636:Mesencephalon / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000066829:Neuroprotection; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011180:Postmortem Changes; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
chemical_list: C095184:CDR2 protein, human; C000623130:Cdr2 protein, rat; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D014446:Tyrosine 3-Monooxygenase; D002154:Calpain; D015655:1-Methyl-4-phenylpyridinium