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

Shimura, Hideki; Hattori, Nobutaka; Kubo, Shin-ichiro; Mizuno, Yoshikuni; Asakawa, Shuichi; Minoshima, Shinsei; Shimizu, Nobuyoshi; Iwai, Kazuhiro; Chiba, Tomoki; Tanaka, Keiji; Suzuki, Toshiaki

doi:10.1038/77060

Cited by 2,024Parkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathwaysNuclear Receptors and Signaling

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

Shimura, Hideki, Hattori, Nobutaka, Kubo, Shin-ichiro, Mizuno, Yoshikuni, Asakawa, Shuichi, Minoshima, Shinsei, Shimizu, Nobuyoshi, Iwai, Kazuhiro +3 more·2000·Nature Genetics

DOI 10.1038/77060

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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 proteins. 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 sclerosis.

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Parkin, the product of PARK2, is known to be a RING-finger-containing E3-Ub ligase.
“Parkin, the product of PARK2, is known to be a RINGfinger-containing E3-Ub ligase”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Shimura et al. 2000
Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD.
“Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD [22,23,24,94,95,96].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [24]

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“Shimura and colleagues have demonstrated that the E2 enzyme associated with Parkin is UbcH7 and that a PD-associated missense mutation (p.T240R) in the first RING domain is sufficient to disrupt this interaction (Shimura et al. 2000).”
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Parkin is linked to the ubiquitin pathway
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[Autosomal recessive juvenile parkinsonism: its pathogenesis is involved in the ubiquitin-proteasome pathway].
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Self-citation
Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1
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Authors: Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., & Suzuki, T.
Affiliations: Juntendo University (JP)
Keio University (JP)
Japan Science and Technology Agency (JP)
Corresponding author: Tanaka, Keiji
ORCID: Shimura, Hideki
Hattori, Nobutaka
Mizuno, Yoshikuni
Asakawa, Shuichi
Chiba, Tomoki
Tanaka, Keiji
Suzuki, Toshiaki
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2000-07
Volume: 25
Issue: 3
Pages: 302-305
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/77060
OpenAlex: W1550876205
Cited by: 2,024
References: 30
Citations by year: 2026: 34 · 2025: 29 · 2024: 49 · 2023: 48 · 2022: 41 · 2021: 54 · 2020: 60 · 2019: 51 · 2018: 57 · 2017: 67 · 2016: 75 · 2015: 72 · 2014: 83 · 2013: 102 · 2012: 98
FWCI: 70.08
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords: Parkin, PARK2, autosomal recessive juvenile parkinsonism, Parkinson's disease, ubiquitin-protein ligase, UbcH7, protein degradation, dopaminergic neuron death, Lewy bodies, neurodegeneration, ubiquitination, Alzheimer's disease, tauopathy, amyotrophic lateral sclerosis
MeSH terms: Humans, Ligases, Parkinson Disease, Recombinant Fusion Proteins, Tumor Cells, Cultured, Ubiquitins, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases

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

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