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Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
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 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
In the citing paper
“Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD).”
From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Shimura et al, 2000
In the citing paper
“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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Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy
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“Parkin is an ubiquitin E3 ligase (Shimura et al., 2000; Zhang et al., 2000).”
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“PINK1 and Parkin are thought to act in a common pathway to promote the autophagic degradation of damaged mitochondria (Dodson and Guo, 2007), in addition to the unique functions of Parkin in the ubiquitin-proteasome pathway (Shimura et al., 2000).”
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“The presence of the RBR domain suggested that parkin acts as an E3 ubiquitin ligase, mediating the covalent attachment of ubiquitin moieties to substrate proteins (Shimura et al , 2000; Zhang et al , 2000).”
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BackgroundInfluentialWhat Genetics Tells us About the Causes and Mechanisms of Parkinson's Disease
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“A juvenile onset autosomal recessive form of PD (AR-JP) is caused by mutation of the Parkin gene, which compromises the ubiquitin ligase function of the protein (Shimura et al., 2000).”
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“…ligase, responsible for the attachment of ubiquitin to substrates such as CDCrel-1, Pael receptor, and, possibly, a glycosylated form of -synuclein (Shimura et al., 2000; Zhang et al., 2000; Imai et al., 2001; Shimura et al., 2001), and UCHL-1 is a member of the family of deubiquitinating enzymes,…”
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“Mutations in PARK2 were reported to impair the E3 ubiquitin ligase activity of parkin [Shimura et al., 2000], which resulted in insufficient protein clearance and the subsequent formation of protein aggregates.”
BackgroundUBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids
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“In matched experiments with UbcH7, neither BRCA1/BARD1 nor E6AP enhance reactivity toward free cysteine (Supplementary Fig 8a, c.) Besides HECT-type ligases, UbcH7 is reported to function with members of the RING E3 family known as RBRs that includes Parkin and HHARI 5,6 .”
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“We and others initially elucidated the function of parkin as a ubiquitin ligase and showed that pathological mutations of parkin impair its catalytic activity (Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000).”
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“Parkin mutations in autosomal recessive juvenile parkinsonism showed a decrease in ubiquitin-ligase enzymatic activity in the substantia nigra (Shimura et al., 2000, 2001), which also support the hypothesis that failure of the UPS leads to the neurodegeneration underlying Parkinson's disease.”
BackgroundThe role of PINK1–Parkin in mitochondrial quality control
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“Discovery of the PINK1–Parkin mitochondrial QC pathway Soon after Parkin was cloned in 1998 it was appreciated to possess an N-terminal UBL and a RING domain 1 , and Parkin was shown to possess E3 ubiquitin ligase activity against model substrates in vitro 141 .”
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“Furthermore, in the case of autosomal recessive juvenile Parkinsonism, parkin mutations can cause a significant decline of ubiquitin-ligase enzymatic activity in the SNpc [86, 87], which can decrease the proteasomal degradation process significantly.”
BackgroundMitochondrial-nuclear communications
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“Parkin encodes for a RING domain– containing ubiquitin E3 ligase (Shimura et al., 2000; Zhang et al., 2000).”
A block of autophagy in lysosomal storage disorders
Settembre, C., Fraldi, A., Jahreiss, L., Spampanato, C., Venturi, C. B., Medina, D. L., de Pablo, R., Tacchetti, C., Rubinsztein, D. C., & Ballabio, A. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm289 · Cited by 509
Hashimoto, M., Rockenstein, E. M., Crews, L. A., & Masliah, E. (2003) · NeuroMolecular Medicine · doi:10.1385/nmm:4:1-2:21 · Cited by 508
“Parkin has since been characterized as ubiquitin E3-ligating enzyme (Shimura et al., 2000), and UCHL-1, which was known to be a ubiquitin carboxyl-terminal hydrolase, also possesses ubiquitin E3 activity through dimer formation (Liu et al.”
BackgroundTanaka, Y. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.9.919 · Cited by 504
“Proteins encloded by other causal genes of familial PD, parkin and UCH-L1, are a ubiquitin-protein ligase and a deubiquitinating enzyme, respectively (16,19).”
BackgroundValente, E. M., Bentivoglio, A. R., Dixon, P. H., Ferraris, A., Ialongo, T., Frontali, M., Albanese, A., & Wood, N. W. (2001) · The American Journal of Human Genetics · doi:10.1086/319522 · Cited by 506
“The Parkin protein appears to be involved in protein degradation, as a ubiquitin-protein ligase interacting with the ubiquitin-conjugating enzyme UbcH7 (Shimura et al. 2000).”
BackgroundPINK1/PARKIN signalling in neurodegeneration and neuroinflammation
Quinn, P. M. J., Moreira, P. I., Ambrósio, A. F., & Alves, C. H. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01062-w · Cited by 503
“PARKIN, also known as PDJ, AR-JP, LPRS2 and PARK2 is localized to chromosome 6 in position 6q26 [61, 62].”
BackgroundLewy bodies and parkinsonism in families with parkin mutations
Farrer, M. J., Chan, P., Chen, R., Tan, L. C. S., Lincoln, S., Hernandez, D. G., Forno, L. S., Gwinn, K. A., Petrucelli, L., Hussey, J., et al. (2001) · Annals of Neurology · doi:10.1002/ana.1132 · Cited by 483
“Parkin is a ubiquitin protein ligase.(7,8) The majority of families described in Japanese, African, and European populations have either homozygous deletions or compound point mutations and deletions, although several small kindreds with hemizygous mutations (affecting one allele of the gene) have also been reported.”
BackgroundGenetics in Parkinson disease: Mendelian versus non‐Mendelian inheritance
Hernandez, D. G., Reed, X., & Singleton, A. B. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13593 · Cited by 448
“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).”
BackgroundShults, C. W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509567103 · Cited by 495
Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K. I., & Takahashi, R. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00583-x · Cited by 477
“…CREST Along with other researchers, we have demonstratedJapan Science and Technology Corporation that Parkin has E3 activity and that AR-JP-linked Parkin4-1-8 Honcho, Kawaguchi mutants are defective in E3 activity (Imai et al., 2000;Saitama 332-0012 Shimura et al., 2000; Zhang et al., 2000).”
BackgroundCHIP-Hsc70 Complex Ubiquitinates Phosphorylated Tau and Enhances Cell Survival
Shimura, H., Schwartz, D., Gygi, S. P., & Kosik, K. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m305838200 · Cited by 469
Self-citationThe expression of DJ-1 (PARK7) in normal human CNS and idiopathic Parkinson's disease
Bandopadhyay, R. (2004) · Brain · doi:10.1093/brain/awh054 · Cited by 475
“Parkin functions as an E3 ubiquitin protein ligase (Shimura et al., 2000) and its levels are low or absent in patients with autosomal recessive juvenile Parkinson's disease (Shimura et al.”
BackgroundRole of Endoplasmic Reticulum Stress in Metabolic Disease and Other Disorders
Özcan, L., & Tabas, I. A. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-043010-144749 · Cited by 468
Ageing as a primary risk factor for Parkinson's disease: evidence from studies of non-human primates
Collier, T. J., Kanaan, N. M., & Kordower, J. H. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3039 · Cited by 469
The pathogenesis of cell death in Parkinson's disease
Jenner, P. G., & Olanow, C. W. (2006) · Neurology · doi:10.1212/wnl.66.10_suppl_4.s24 · Cited by 451
Pesah, Y., Pham, T., Burgess, H., Middlebrooks, B. W., Verstreken, P., Zhou, Y., Harding, M. J., Bellen, H. J., & Mardon, G. (2004) · Development · doi:10.1242/dev.01095 · Cited by 448
“In addition, Parkin can promote the ubiquitination and degradation of an O-glycosylated form of α-Synuclein (Shimura et al., 2000).”
Endoplasmic reticulum dysfunction in neurological disease
Roussel, B. D., Kruppa, A. J., Miranda, E., Crowther, D. C., Lomas, D. A., & Marciniak, S. J. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70238-7 · Cited by 441
Mhyre, T. R., Boyd, J. T., Hamill, R. W., & Maguire‐Zeiss, K. A. (2012) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-5416-4_16 · Cited by 463
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript E3-ubiquitin ligase (Shimura et al. 2000), which can interact with a number of binding partners.”
BackgroundRecent Advances in the Genetics of Parkinson's Disease
Martin, I., Dawson, V. L., & Dawson, T. M. (2011) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082410-101440 · Cited by 451
“Most parkin mutations impact its E3 ligase activity or interactions with E2 enzymes such as UbcH7 and UbcH8, leading to a loss of parkin function (116, 140).”
Modification of Brain Aging and Neurodegenerative Disorders by Genes, Diet, and Behavior
Mattson, M. P., Chan, S. L., & Duan, W. (2002) · Physiological Reviews · doi:10.1152/physrev.00004.2002 · Cited by 440
Morais, V. A., Verstreken, P., Röthig, A. H. J., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W. J., Weisenhorn, D. M. V., et al. (2009) · EMBO Molecular Medicine · doi:10.1002/emmm.200900006 · Cited by 462
“Parkin, an E3 ubiquitin ligase, is another gene implicated in autosomal recessive PD (Shimura et al, 2000).”
Smith, W. W., Pei, Z., Jiang, H., Moore, D. J., Liang, Y., West, A. B., Dawson, V. L., Dawson, T. M., & Ross, C. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508052102 · Cited by 427
Whitworth, A. J., Theodore, D. A., Greene, J. C., Beneš, H., Wes, P. D., & Pallanck, L. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501078102 · Cited by 421
Astrocytes in Neurodegenerative Disease: Table 1.
Phatnani, H., & Maniatis, T. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a020628 · Cited by 420
“Chronic MPTP/P injections in these mice led to an increased UPR (both ATF6a and PERK/ eIF2a/ATF4 branches).”
BackgroundInfluentialVeeriah, S., Taylor, B. S., Meng, S., Fang, F., Yilmaz, E., Vivanco, I., Janakiraman, M., Schultz, N. D., Hanrahan, A. J., Pao, W. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.491 · Cited by 414
Metadata
- 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
- Venue
- Nature Genetics
- Published
- 2000-07
- Volume
- 25
- Issue
- 3
- Pages
- 302-305
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- 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 › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 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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