Nature Genetics
25, 302 - 305 (2000)
doi:10.1038/77060
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligaseHideki Shimura1, 2, Nobutaka Hattori1, Shin-ichiro Kubo1, Yoshikuni Mizuno1, Shuichi Asakawa3, Shinsei Minoshima3, Nobuyoshi Shimizu3, Kazuhiro Iwai4, Tomoki Chiba2, Keiji Tanaka2
& Toshiaki Suzuki21
Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. 2
Tokyo Metropolitan Institute of Medical Science and CREST, Japan Science and Technology Corporation (JST), Bunkyo-ku, Tokyo, Japan. 3
Department of Molecular Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. 4
Department of Molecular and System Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Correspondence should be addressed to Keiji Tanaka tanakak@rinshoken.or.jpAutosomal 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,
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