Abstract
Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Dynamins
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GTP Phosphohydrolases / genetics
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GTP Phosphohydrolases / metabolism*
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Gene Expression Regulation, Enzymologic / genetics
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HeLa Cells
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Humans
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondria / pathology
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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Mutation
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Parkinson Disease / genetics
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Parkinson Disease / metabolism*
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Parkinson Disease / pathology
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism*
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Ubiquitin-Protein Ligases / biosynthesis*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitination*
Substances
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Microtubule-Associated Proteins
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Mitochondrial Proteins
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Ubiquitin-Protein Ligases
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parkin protein
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Proteasome Endopeptidase Complex
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GTP Phosphohydrolases
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DNM1L protein, human
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Dynamins