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Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase

Nature Genetics volume 25, pages 302–305 (2000)Cite this article

Abstract

Autosomal recessive juvenile parkinsonism (AR–JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins1. We previously cloned PARK2, mutations of which cause AR–JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR–JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis3,4,5,6,7,8,9,10.

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Figure 1: Association of parkin with UbcH7 in human embryonic kidney 293 cells.
Figure 2: Domain analysis of parkin interacting with UbcH7.
Figure 3: Association of ubiquitinated cellular proteins with parkin after treatment with MG132 in human dopaminergic neuroblastoma SH-SY5Y cells.
Figure 4: Domain analysis of parkin required for the binding of ubiquitinated proteins.
Figure 5: Parkin exhibits ubiquitination activity in vitro.
Figure 6: Model of the parkin-directed ubiquitination pathway.

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Acknowledgements

We thank E. Melamed for the DNA sample with a mutation in the Ubl domain.

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Authors and Affiliations

  1. Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan

    Hideki Shimura, Nobutaka Hattori, Shin-ichiro Kubo & Yoshikuni Mizuno

  2. Tokyo Metropolitan Institute of Medical Science and CREST, Japan Science and Technology Corporation (JST), Bunkyo-ku, Tokyo, Japan

    Hideki Shimura, Tomoki Chiba, Keiji Tanaka & Toshiaki Suzuki

  3. Department of Molecular Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan

    Shuichi Asakawa, Shinsei Minoshima & Nobuyoshi Shimizu

  4. Department of Molecular and System Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Kazuhiro Iwai

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Correspondence to Keiji Tanaka.

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Shimura, H., Hattori, N., Kubo, Si. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25, 302–305 (2000). https://doi.org/10.1038/77060

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