Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration

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, Kwang Chul Chung, K. Kim, Young Jun Oh

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Article numbere2240
JournalCell Death and Disease
Volume7
Issue number6
DOIs
Publication statusPublished - 2016 Jun 2

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Proteins
1-Methyl-4-phenylpyridinium
Calcium-Binding Proteins
Calpain
Tyrosine 3-Monooxygenase
Parkinsonian Disorders
Enzyme Inhibitors
Proteasome Endopeptidase Complex
Mesencephalon
Ubiquitin
Neurodegenerative Diseases
Autoantibodies
Parkinson Disease
Neoplasms
Theoretical Models
Central Nervous System
Pharmacology
T-Lymphocytes
Neurons
Injections

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Hwang, J. Y. ; Lee, J. ; Oh, C. K. ; Kang, H. W. ; Hwang, I. Y. ; Um, J. W. ; Park, H. C. ; Kim, S. ; Shin, J. H. ; Park, W. Y. ; Darnell, R. B. ; Um, H. D. ; Chung, Kwang Chul ; Kim, K. ; Oh, Young Jun. / Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration. In: Cell Death and Disease. 2016 ; Vol. 7, No. 6.
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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.",
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Hwang, JY, Lee, J, Oh, CK, Kang, HW, Hwang, IY, Um, JW, Park, HC, Kim, S, Shin, JH, Park, WY, Darnell, RB, Um, HD, Chung, KC, Kim, K & Oh, YJ 2016, 'Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration', Cell Death and Disease, vol. 7, no. 6, e2240. https://doi.org/10.1038/cddis.2016.151

Proteolytic degradation and potential role of onconeural protein cdr2 in neurodegeneration. / Hwang, J. Y.; Lee, J.; Oh, C. K.; Kang, H. W.; Hwang, I. Y.; Um, J. W.; Park, H. C.; Kim, S.; Shin, J. H.; Park, W. Y.; Darnell, R. B.; Um, H. D.; Chung, Kwang Chul; Kim, K.; Oh, Young Jun.

In: Cell Death and Disease, Vol. 7, No. 6, e2240, 02.06.2016.

Research output: Contribution to journalArticle

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AU - Hwang, J. Y.

AU - Lee, J.

AU - Oh, C. K.

AU - Kang, H. W.

AU - Hwang, I. Y.

AU - Um, J. W.

AU - Park, H. C.

AU - Kim, S.

AU - Shin, J. H.

AU - Park, W. Y.

AU - Darnell, R. B.

AU - Um, H. D.

AU - Chung, Kwang Chul

AU - Kim, K.

AU - Oh, Young Jun

PY - 2016/6/2

Y1 - 2016/6/2

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