Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Se Jung Kim, Jee Young Sung, Ji Won Um, Nobutaka Hattori, Yoshikuni Mizuno, Keiji Tanaka, Seung R. Paik, Jongsun Kim, Kwang Chul Chung

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Mutations in the α-synuclein and parkin genes cause heritable forms of Parkinson's disease. In the present study, we examined the possible functional relationship between the parkin and α-synuclein genes in a conditionally immortalized embryonic hippocampal cell (H19-7) line. Whereas transient transfection of α-synuclein into neuronal H19-7 cells caused the formation of its intracytoplasmic inclusions and a significant cell death, the combined overexpression of parkin restored the α-synuclein-induced decrease in cell viability to control levels. In addition, the overexpression of parkin was found to generate selective cleavage of α-synuclein. Furthermore, the cytoprotective effect of parkin on α-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor. Interestingly, the overexpression of parkin induced the activation of an intracellular cysteine protease, calpain, but not caspase, and the cytoprotective effect of parkin on α-synuclein cytotoxicity was significantly inhibited by the presence of calpain-specific inhibitors. In conclusion, our results suggest that parkin accelerates the degradation of α-synuclein via the activation of the nonproteasomal protease, calpain, leading to the prevention of α-synuclein-induced cell death in embryonic hippocampal progenitor cells.

Original languageEnglish
Pages (from-to)41890-41899
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number43
DOIs
Publication statusPublished - 2003 Oct 24

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Synucleins
Calpain
Chemical activation
Cell death
Cell Death
Genes
Proteasome Inhibitors
Cysteine Proteases
Level control
Cytotoxicity
Caspases
Transfection
Parkinson Disease
Cell Survival
Peptide Hydrolases
Stem Cells
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kim, Se Jung ; Sung, Jee Young ; Um, Ji Won ; Hattori, Nobutaka ; Mizuno, Yoshikuni ; Tanaka, Keiji ; Paik, Seung R. ; Kim, Jongsun ; Chung, Kwang Chul. / Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 43. pp. 41890-41899.
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Kim, SJ, Sung, JY, Um, JW, Hattori, N, Mizuno, Y, Tanaka, K, Paik, SR, Kim, J & Chung, KC 2003, 'Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain', Journal of Biological Chemistry, vol. 278, no. 43, pp. 41890-41899. https://doi.org/10.1074/jbc.M306017200

Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain. / Kim, Se Jung; Sung, Jee Young; Um, Ji Won; Hattori, Nobutaka; Mizuno, Yoshikuni; Tanaka, Keiji; Paik, Seung R.; Kim, Jongsun; Chung, Kwang Chul.

In: Journal of Biological Chemistry, Vol. 278, No. 43, 24.10.2003, p. 41890-41899.

Research output: Contribution to journalArticle

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AU - Kim, Jongsun

AU - Chung, Kwang Chul

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AB - Mutations in the α-synuclein and parkin genes cause heritable forms of Parkinson's disease. In the present study, we examined the possible functional relationship between the parkin and α-synuclein genes in a conditionally immortalized embryonic hippocampal cell (H19-7) line. Whereas transient transfection of α-synuclein into neuronal H19-7 cells caused the formation of its intracytoplasmic inclusions and a significant cell death, the combined overexpression of parkin restored the α-synuclein-induced decrease in cell viability to control levels. In addition, the overexpression of parkin was found to generate selective cleavage of α-synuclein. Furthermore, the cytoprotective effect of parkin on α-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor. Interestingly, the overexpression of parkin induced the activation of an intracellular cysteine protease, calpain, but not caspase, and the cytoprotective effect of parkin on α-synuclein cytotoxicity was significantly inhibited by the presence of calpain-specific inhibitors. In conclusion, our results suggest that parkin accelerates the degradation of α-synuclein via the activation of the nonproteasomal protease, calpain, leading to the prevention of α-synuclein-induced cell death in embryonic hippocampal progenitor cells.

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