The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Hershko, A., & Ciechanover, A. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.425 · Cited by 8,840
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., Yokochi, M., Mizuno, Y., & Shimizu, N. (1998) · Nature · doi:10.1038/33416 · Cited by 5,227
Self-citationAlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schols, L., & Riess, O. (1998) · Nature Genetics · doi:10.1038/ng0298-106 · Cited by 3,836
Rock, K. L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D., & Goldberg, A. L. (1994) · Cell · doi:10.1016/s0092-8674(94)90462-6 · Cited by 2,524
Aggregation of Huntingtin in Neuronal Intranuclear Inclusions and Dystrophic Neurites in Brain
DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., & Aronin, N. (1997) · Science · doi:10.1126/science.277.5334.1990 · Cited by 2,439
STRUCTURE AND FUNCTIONS OF THE 20S AND 26S PROTEASOMES
Coux, O., Tanaka, K., & Goldberg, A. L. (1996) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.65.070196.004101 · Cited by 2,438
Self-citationUBIQUITIN-DEPENDENT PROTEIN DEGRADATION
Hochstrasser, M. (1996) · Annual Review of Genetics · doi:10.1146/annurev.genet.30.1.405 · Cited by 1,706
The ubiquitin pathway in Parkinson's disease
Leroy, E., Boyer, R., Auburger, G. W. J., Leube, B., Ulm, G., Mezey, É., Harta, G., Brownstein, M., Jonnalagada, S., Chernova, T., et al. (1998) · Nature · doi:10.1038/26652 · Cited by 1,599
Flagged first, then by citations
Cited by
Sorted by citations
Items 101–200 of 1,004
Parkin prevents mitochondrial swelling and cytochrome c release in mitochondria-dependent cell death
Darios, F. D. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg044 · Cited by 407
“Several parkin mutations found in patients with autosomal recessive early-onset parkinsonism impair this activity (9,11).”
BackgroundThe three ‘P’s of mitophagy: PARKIN.; PINK1.; and post-translational modifications
Durcan, T. M., & Fon, E. A. (2015) · Genes & Development · doi:10.1101/gad.262758.115 · Cited by 400
p62/SQSTM1 cooperates with Parkin for perinuclear clustering of depolarized mitochondria
Okatsu, K., Saisho, K., Shimanuki, M., Nakada, K., Shitara, H., Sou, Y., Kimura, M., Sato, S., Hattori, N., Komatsu, M., et al. (2010) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01426.x · Cited by 397
“One familial form of the PD gene causing autosomal recessive juvenile Parkinsonism (AR-JP) is Parkin (also known as PARK2), which encodes an E3 ubiquitin ligase, a substrate recognition member of the ubiquitylation pathway (Kitada et al. 1998; Shimura et al. 2000).”
BackgroundSelf-citationGenetic and environmental factors in the cause of Parkinson's disease
Warner, T. T., & Schapira, A. H. V. (2003) · Annals of Neurology · doi:10.1002/ana.10487 · Cited by 406
“terminus and two RING finger domains in its C terminus.(44) Molecular studies have determined that par-”
BackgroundThe role of parkin in familial and sporadic Parkinson's disease
Dawson, T. M., & Dawson, V. L. (2010) · Movement Disorders · doi:10.1002/mds.22798 · Cited by 411
“There is one report that the interaction of parkin with alpha-synuclein requires posttranslation modification, but this has not been replicated.(25) Thus, how parkin overexpression prevents a-synuclein toxicity is unclear.”
BackgroundParkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation
Xiong, H., Wang, D., Chen, L., Choo, Y. S., Ma, H., Tang, C., Xia, K., Jiang, W. B., Ronai, Z. A., Zhuang, X., et al. (2009) · Journal of Clinical Investigation · doi:10.1172/jci37617 · Cited by 406
Ardley, H. C., & Robinson, P. A. (2005) · Essays in Biochemistry · doi:10.1042/eb0410015 · Cited by 401
“Parkin mutations are responsible for more than 50% of all cases of AR-JP (autosomal recessive juvenile Parkinsonism) [22–24].”
BackgroundAxon pathology in neurological disease: a neglected therapeutic target
Coleman, M. P., & Perry, V. H. (2002) · Trends in Neurosciences · doi:10.1016/s0166-2236(02)02255-5 · Cited by 387
Calpain-Mediated Signaling Mechanisms in Neuronal Injury and Neurodegeneration
Vosler, P. S., Brennan, C. S., & Chen, J. (2008) · Molecular Neurobiology · doi:10.1007/s12035-008-8036-x · Cited by 394
Staropoli, J. F., McDermott, C., Martinat, C., Schulman, B. A., Demireva, E. Y., & Abeliovich, A. (2003) · Neuron · doi:10.1016/s0896-6273(03)00084-9 · Cited by 388
Imaizumi, Y., Okada, Y., Akamatsu, W., Koike, M., Kuzumaki, N., Hayakawa, H., Nihira, T., Kobayashi, T., Ohyama, M., Sato, S., et al. (2012) · Molecular Brain · doi:10.1186/1756-6606-5-35 · Cited by 385
“It encodes a component of an E3 ubiquitin ligase involved in mitochondrial homeostasis [1-5].”
BackgroundSelf-citationUSP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin
Durcan, T. M., Tang, M. Y., Pérusse, J. R., Dashti, E. A., Aguileta, M. A., McLelland, G., Gros, P., Shaler, T. A., Faubert, D., Coulombe, B., et al. (2014) · The EMBO Journal · doi:10.15252/embj.201489729 · Cited by 375
“Mutations in the Park2 gene are associated with a familial form of Parkinson’s disease (PD) and are believed to impair the normal function of the parkin protein as an E3 ubiquitin (Ub)-ligase (Shimura et al , 2000).”
Parkin Ubiquitinates Drp1 for Proteasome-dependent Degradation
Wang, H., Song, P., Du, L., Tian, W., Yue, W., Liu, M., Li, D., Wang, B., Zhu, Y., Cao, C., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.144238 · Cited by 392
Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases
Riley, B. E., Lougheed, J. C., Callaway, K., Velasquez, M., Brecht, E., Nguyen, L., Shaler, T. A., Walker, D., Yang, Y., Regnström, K. J., et al. (2013) · Nature Communications · doi:10.1038/ncomms2982 · Cited by 378
CD36 tango in cancer: signaling pathways and functions
Wang, J., & Li, Y. (2019) · Theranostics · doi:10.7150/thno.36037 · Cited by 369
“However, because parkin can also trigger polyubiquitylation, parkin functions vary in different tissues [73].”
BackgroundTargeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control
Narendra, D. P., & Youle, R. J. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3799 · Cited by 367
“activity in vitro (4, 43), disrupt recruitment of Parkin to mitochondria (11, 25, 31).”
BackgroundParkin Suppresses Dopaminergic Neuron-Selective Neurotoxicity Induced by Pael-R in Drosophila
Yang, Y., Nishimura, I., Imai, Y., Takahashi, R., & Lu, B. (2003) · Neuron · doi:10.1016/s0896-6273(03)00143-0 · Cited by 367
Parkinsonian Mimetics Induce Aspects of Unfolded Protein Response in Death of Dopaminergic Neurons
Holtz, W. A., & O’Malley, K. L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211821200 · Cited by 368
Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron
Osaka, H. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg211 · Cited by 364
“substrates (26,27), causing substrate accumulation and toxicity to neurons at the substantia nigra.”
BackgroundNeuronal cell death in neurodegenerative diseases: recurring themes around protein handling
Gorman, A. M. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00402.x · Cited by 362
“The PD-associated gene parkin is an E3 ligase, involved in the addition of ubiquitin chains to a select number of protein substrates [159, 160].”
Nikolaev, A. Y., Li, M., Puskas, N., Qin, J., & Gu, W. J. (2003) · Cell · doi:10.1016/s0092-8674(02)01255-2 · Cited by 358
Fallon, L., Bélanger, C. M. L., Corera, A. T., Kontogiannea, M., Regan-Klapisz, E., Moreau, F., Voortman, J., Haber, M., Rouleau, G., Thorarinsdottir, T., et al. (2006) · Nature Cell Biology · doi:10.1038/ncb1441 · Cited by 317
Efp targets 14-3-3σ for proteolysis and promotes breast tumour growth
Urano, T., Saito, T., Tsukui, T., Fujita, M., Hosoi, T., Muramatsu, M., Ouchi, Y., & Inoue, S. (2002) · Nature · doi:10.1038/nature00826 · Cited by 357
Deadly encounter: ubiquitin meets apoptosis
Jesenberger, V., & Jentsch, S. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm731 · Cited by 353
Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases
Nakamura, T., Tu, S., Akhtar, M. W., Sunico, C. R., Okamoto, S., & Lipton, S. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.05.005 · Cited by 361
“S-Nitrosylation of Parkin Parkin is an E3 ubiquitin ligase that participates in the ubiquitinproteasome system (UPS) responsible for targeting specific proteins for degradation (Shimura et al., 2000).”
Parkin disease: a phenotypic study of a large case series
Khan, N. L., Graham, E., Critchley, P., Schrag, A. E., Wood, N. W., Lees, A. J., Bhatia, K. P., & Quinn, N. P. (2003) · Brain · doi:10.1093/brain/awg142 · Cited by 352
“ubiquitin-protein ligase through the C-terminal ring ®nger domain; mutants have impaired self-ubiquitination and impaired degradation of both self and synaptic vesicle associated protein (Shimura et al., 2000; Zhang et al., 2000).”
BackgroundOueslati, A., Fournier, M., & Lashuel, H. A. (2010) · Progress in brain research · doi:10.1016/s0079-6123(10)83007-9 · Cited by 354
Loss of locus coeruleus neurons and reduced startle in parkin null mice
von Coelln, R., Thomas, B., Savitt, J. M., Lim, K. L., Sasaki, M., Hess, E. J., Dawson, V. L., & Dawson, T. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401297101 · Cited by 353
Autoregulation of Parkin activity through its ubiquitin‐like domain
Chaugule, V. K., Burchell, L., Barber, K. R., Sidhu, A., Leslie, S. J., Shaw, G. S., & Walden, H. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.204 · Cited by 339
“Parkin, the product of the parkin gene, has E3-ubiquitinligase activity (Shimura et al, 2000; Zhang et al, 2000).”
BackgroundResultInfluentialZhou, W., & Freed, C. R. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507124200 · Cited by 355
The two-century journey of Parkinson disease research
Przedborski, S. (2017) · Nature reviews. Neuroscience · doi:10.1038/nrn.2017.25 · Cited by 354
Betarbet, R. S., Canet-Aviles, R., Sherer, T., Mastroberardino, P. G., McLendon, C., Kim, J.-H., Lund, S. A., Na, H. M., Taylor, G., Bence, N., et al. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.12.003 · Cited by 344
Rana, A., Rera, M., & Walker, D. W. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1216197110 · Cited by 335
“Studies of genes involved in heritable forms of PD, including Parkin an E3 ubiquitin ligase (12), have greatly influenced our understanding of the molecular mechanisms underlying neurodegeneration in this disorder (13).”
BackgroundStructure of the human Parkin ligase domain in an autoinhibited state
Wauer, T., & Komander, D. (2013) · The EMBO Journal · doi:10.1038/emboj.2013.125 · Cited by 328
“The molecular requirements for RING–E2 interactions have by now been studied for several E3–E2 combinations, such as the c-cbl–UBE2L3 interaction (Zheng et al , 2000).”
InfluentialParkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells
Suen, D., Narendra, D. P., Tanaka, A., Manfredi, G., & Youle, R. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914569107 · Cited by 345
“We recently found that the cytosolic E3 ligase, Parkin, which is commonly mutated in autosomal-recessive juvenile parkinsonism (8, 9) and has been linked to mitochondrial maintenance in Drosophila (10–13) and in mouse (14, 15), can translocate to depolarized mitochondria and activate their elimination by autophagy.”
BackgroundOlzmann, J. A., Li, L., Chudaev, M. V., Chen, J., Perez, F. A., Palmiter, R. D., & Chin, L. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200611128 · Cited by 343
“In vitro ubiquitination assays were performed using a well-established reconstitution system (Shimura et al., 2000, 2001; Pridgeon et al., 2003).”
MethodJohnson, M., & Bobrovskaya, L. (2014) · NeuroToxicology · doi:10.1016/j.neuro.2014.12.002 · Cited by 344
Proteasomal degradation of tau protein
David, D. C., Layfield, R., Serpell, L., Narain, Y., Goedert, M., & Spillantini, M. G. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01137.x · Cited by 327
“…in the ubiquitin-dependent proteasomal degradative pathway cause some familial neurodegenerative diseases (Leroy et al. 1998; Saigoh et al. 1999; Shimura et al. 2000) strongly suggests that altered function of this pathway could be one of the mechanisms leading to neurodegeneration (reviewed in…”
BackgroundImpaired mitochondrial dynamics and function in the pathogenesis of Parkinson's disease
Büeler, H. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.03.006 · Cited by 332
“degradation of several proteins in vitro (Shimura et al., 2000; Zhang et al., 2000; Imai et al., 2001; Corti et al., 2003).”
Understanding the molecular causes of Parkinson's disease
Wood‐Kaczmar, A., Gandhi, S., & Wood, N. W. (2006) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2006.09.007 · Cited by 334
Parkin Localizes to the Lewy Bodies of Parkinson Disease and Dementia with Lewy Bodies
Schlossmacher, M. G., Frosch, M. P., Gai, W., Medina, M., Sharma, N., Forno, L. S., Ochiishi, T., Shimura, H., Sharon, R., Hattori, N., et al. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61113-3 · Cited by 330
“29 The abundance of parkin in postsynaptic fractions of adult rat brain (Figure 8a) suggests that binding partners (including Ub-conjugating enzymes other than UbcH7) and substrates also exist at this site.”
BackgroundInfluentialSelf-citationBianco, C. L., Schneider, B. L., Bauer, M., Sajadi, A., Brice, A., Iwatsubo, T., & Aebischer, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0405313101 · Cited by 329
The Role of Innate and Adaptive Immunity in Parkinson's Disease
Kannarkat, G. T., Boss, J. M., & Tansey, M. G. (2013) · Journal of Parkinson’s Disease · doi:10.3233/jpd-130250 · Cited by 324
“Potential roles for this protein are in preventing protein aggregation and/or promoting mitophagy [167–169].”
BackgroundUnfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders
Doyle, K., Kennedy, D. C., Gorman, A. M., Gupta, S., Healy, S., & Samali, A. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01374.x · Cited by 329
“Several genetic mutations have been linked to the recessive form of PD including Parkin, an E3 ligase which forms part of the cascade reaction which targets misfolded proteins for degradation by the proteasome [84].”
BackgroundGenetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases
Migliore, L., & Coppedè, F. (2008) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2008.10.011 · Cited by 331
RBR E3 ubiquitin ligases: new structures, new insights, new questions
Spratt, D. E., Walden, H., & Shaw, G. S. (2014) · Biochemical Journal · doi:10.1042/bj20140006 · Cited by 335
Parkin-Independent Mitophagy Controls Chemotherapeutic Response in Cancer Cells
Villa, E., Proïcs, E., Rubio‐Patiño, C., Obba, S., Zunino, B., Bossowski, J. P., Rozier, R., Chiche, J., Mondragón, L., Riley, J. S., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.087 · Cited by 325
“The ubiquitin (Ub) E3 ligase Parkin, which is mutated in recessive familial forms of Parkinson’s disease, is a key mediator of mitochondrial quality control processes (Kitada et al., 1998; Shimura et al., 2000).”
BackgroundPINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol
Sekine, S., & Youle, R. J. (2018) · BMC Biology · doi:10.1186/s12915-017-0470-7 · Cited by 320
“PINK1 is targeted to mitochondria [1], whereas Parkin is located in the cytosol [5, 6].”
BackgroundCesari, R., Martin, E. S., Calin, G. A., Pentimalli, F., Bichi, R., McAdams, H., Trapasso, F., Drusco, A., Shimizu, M., Masciullo, V., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0931262100 · Cited by 314
Tofaris, G. K., Layfield, R., & Spillantini, M. G. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)03115-5 · Cited by 363
Wilson, M. A., Collins, J. L., Hod, Y., Ringe, D., & Petsko, G. A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1133288100 · Cited by 319
Alexander, A. G., Marfil, V., & Li, C. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00279 · Cited by 310
“Parkin (human PARK2) is a component of an ubiquitin E3 ligase that is part of the proteasome complex (Shimura et al., 2000).”
BackgroundRETRACTED: Glycogen synthase kinase 3β (GSK3β) mediates 6‐ hydroxydopamine‐induced neuronal death
Chen, G., Bower, K. A., Ma, C., Fang, S., Thiele, C. J., & Luo, J. (2004) · The FASEB Journal · doi:10.1096/fj.04-1551fje · Cited by 311
“Recent genetic evidence implies that ER stress is associated with Parkinson’s disease (PD) (6, 7).”
BackgroundRetractedDeciphering the role of heterozygous mutations in genes associated with parkinsonism
Klein, C., Lohmann-Hedrich, K., Rogaeva, E. A., Schlossmacher, M. G., & Lang, A. E. (2007) · The Lancet Neurology · doi:10.1016/s1474-4422(07)70174-6 · Cited by 309
Baquet, Z. C., Bickford, P. C., & Jones, K. R. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4601-04.2005 · Cited by 318
“In ϳ10% of cases, the disease is associated with a genetic defect (Goldman and Tanner, 1998) in genes, including ␣-synuclein, parkin, or DJ-1 (Feany and Bender, 2000; Shimura et al., 2000; Lotharius and Brundin, 2002).”
BackgroundGenetics of Parkinson's disease and parkinsonism
Hardy, J., Cai, H., Cookson, M., Gwinn, K. A., & Singleton, A. (2006) · Annals of Neurology · doi:10.1002/ana.21022 · Cited by 312
The Genetics of Parkinson Disease
Bekris, L. M., Mata, I. F., & Zabetian, C. P. (2010) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/0891988710383572 · Cited by 314
“The RBR domain interacts with ubiquitin-conjugating enzymes (E2s) to catalyze attachment of ubiquitin to protein targets, thus tagging these proteins for destruction by the proteosome.(100,101) Many ubiquitination substrates have been proposed for parkin including the aminoacyl-tRNA synthetase cofactor, p38, and a rar…”
BackgroundNeuroinflammation and oxidative stress: Co-conspirators in the pathology of Parkinson’s disease
Taylor, J. M., Main, B. S., & Crack, P. J. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2012.12.016 · Cited by 313
“Parkin functions as an E3-ubiqutin ligase conjugating ubiquitin to misfolded or toxic proteins for degradation by the 26S proteasome (Shimura et al., 2000).”
BackgroundLewy-body formation is an aggresome-related process: a hypothesis
Olanow, C. W., Perl, D. P., Demartino, G., & McNaught, K. S. P. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00827-0 · Cited by 312
Oxidative and nitrosative stress in Parkinson's disease
Tsang, A. H. K., & Chung, K. K. K. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.12.006 · Cited by 300
How much phenotypic variation can be attributed to parkin genotype?
Lohmann, E., Periquet, M., Bonifati, V., Wood, N. W., Michele, G. D., Bonnet, A., Fraix, V., Broussolle, E., Horstink, M. W. I. M., Vidailhet, M., et al. (2003) · Annals of Neurology · doi:10.1002/ana.10613 · Cited by 304
“ligase activity, linking parkin-associated PD to a defect in the ubiquitin-proteasome system.(22) Because muta-”
BackgroundZhu, J., Wang, K. Z. Q., & Chu, C. T. (2013) · Autophagy · doi:10.4161/auto.24135 · Cited by 303
Parkin mutations are frequent in patients with isolated early‐onset parkinsonism
Periquet, M., Latouche, M., Lohmann, E., Rawal, N., Michele, G. D., Ricard, S., Teive, H. A. G., Fraix, V., Vidailhet, M., Nicholl, D. J., et al. (2003) · Brain · doi:10.1093/brain/awg136 · Cited by 296
“Parkin is an E3 ubiquitin-protein ligase (Shimura et al., 2000) that ubiquitinates speci®c substrates that are targeted for their degradation through the ubiquitin±proteasome pathway (Joazeiro and Weissman, 2000).”
BackgroundCrosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis
Liu, L., Li, Y., Chen, G., & Chen, Q. (2023) · Journal of Biomedical Science · doi:10.1186/s12929-023-00975-7 · Cited by 322
“Parkin is a cytosolic E3 ubiquitin ligase, and mutations in Parkin genes are responsible for the pathogenesis of autosomal recessive parkinsonism (ARP) [164, 165].”
BackgroundMolecular pathogenesis of Parkinson disease: insights from genetic studies
Gasser, T. (2009) · Expert Reviews in Molecular Medicine · doi:10.1017/s1462399409001148 · Cited by 294
Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps
Levy, O. A., Malagelada, C., & Greene, L. A. (2009) · APOPTOSIS · doi:10.1007/s10495-008-0309-3 · Cited by 300
“Parkin is an E3 ligase, and PD-related mutations cause a decrease in ligase activity [57].”
BNIP3 Protein Suppresses PINK1 Kinase Proteolytic Cleavage to Promote Mitophagy
Zhang, T., Xue, L., Li, L., Tang, C., Wan, Z., Wang, R., Tan, J., Tan, Y., Han, H., Tian, R., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.733410 · Cited by 293
Ko, H. S., Lee, Y., Shin, J., Karuppagounder, S. S., Gadad, B. S., Koleske, A. J., Pletniková, O., Troncoso, J. C., Dawson, V. L., & Dawson, T. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006083107 · Cited by 286
“Parkin is a ubiquitin E3 ligase, and familial mutations are thought to impair the E3 ligase activity of parkin (4, 5).”
BackgroundParkin binds to alpha/beta tubulin and increases their ubiquitination and degradation.
Ren, Y., Zhao, J., & Feng, J. (2003) · PubMed · Cited by 285
Silva, R. M., Ries, V., Oo, T. F., Yarygina, O., Jackson-Lewis, V. R., Ryu, E. J., Lu, P. D., Marciniak, S. J., Ron, D., Przedborski, S., et al. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03428.x · Cited by 290
“These mutations have been implicated in abnormal protein processing because parkin is an E3 ubiquitin-ligase (Shimura et al. 2000) and, as such, it plays a role in targeting cellular proteins for destruction by the proteasome (Ciechanover 1998).”
BackgroundEffects of hydrogen sulfide on mitochondrial function and cellular bioenergetics
Paul, B. D., Snyder, S. H., & Kashfi, K. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101772 · Cited by 289
Tsai, Y. C., Fishman, P. S., Thakor, N. V., & Oyler, G. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212235200 · Cited by 282
The regulation of mitochondrial morphology: Intricate mechanisms and dynamic machinery
Palmer, C. S., Osellame, L. D., Stojanovski, D., & Ryan, M. T. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.05.021 · Cited by 300
Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease
Dodson, M. W., & Guo, M. (2007) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2007.04.010 · Cited by 281
“The Parkin protein bears two RING-finger motifs and has E3 ubiquitin ligase activity in vitro [3].”
BackgroundThe genetic background of Parkinson's disease: current progress and future prospects
Kalinderi, K., Bostantjopoulou, S., & Fidani, L. (2016) · Acta Neurologica Scandinavica · doi:10.1111/ane.12563 · Cited by 304
“The loss-of-function effect of Parkin mutations result in inactivation of its E3 ligase function, failure of ubiquitination of the targeted proteins and therefore a toxic build-up of proteins that are no longer effectively degraded by the parkindependent ubiqutin/proteosome pathway (61).”
BackgroundAggresome‐related biogenesis of Lewy bodies
McNaught, K. S. P., Shashidharan, P., Perl, D. P., Jenner, P. G., & Olanow, C. W. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02301.x · Cited by 279
“…is supported by the paucity of Lewy bodies in parkin-linked autosomal recessive juvenile parkinsonism (AR-JP) patients and by the observation of reduced formation of Lewy body-like inclusions in cultured cells where the ubiquitination cycle is inhibited (Shimura et al., 2000; Chung et al., 2001).”
BackgroundParkin Interacts with Ambra1 to Induce Mitophagy
Van Humbeeck, C., Cornelissen, T., Hofkens, H., Mandemakers, W., Gevaert, K., De Strooper, B., & Vandenberghe, W. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1917-11.2011 · Cited by 287
“Because Parkin is an E3 ubiquitin ligase (Shimura et al., 2000), we asked whether Ambra1 might be a substrate for Parkinmediated ubiquitination.”
BackgroundRideout, H. J., Larsen, K. E., Sulzer, D., & Stefanis, L. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00474.x · Cited by 283
“…Lewy body disease; DMSO, dimethyl sulfoxide; NGF, nerve growth factor; PAGE, polyacrylamide gel electrophoresis; PD, Parkinson's disease; PSI, ZIE[O-tBu]-A-leucinal; SDS, sodium dodecyl sulfate; UCH-L1, ubiquitin C-terminal hydrolase L1. or diminish parkin's E3-like activity (Shimura et al. 2000).”
Aging and Parkinson's disease: Different sides of the same coin?
Collier, T. J., Kanaan, N. M., & Kordower, J. H. (2017) · Movement Disorders · doi:10.1002/mds.27037 · Cited by 291
Lotharius, J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.20.2395 · Cited by 273
Parkin enhances mitochondrial biogenesis in proliferating cells
Kuroda, Y., Mitsui, T., Kunishige, M., Shono, M., Akaike, M., Azuma, H., & Matsumoto, T. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl006 · Cited by 268
“RING-finger proteins, such as parkin, play critical roles in mediating the transfer of ubiquitin to heterologous substrates by presenting a RING-finger domain as an E2 binding site (3,4,21).”
BackgroundUCHL1 (PGP 9.5): Neuronal biomarker and ubiquitin system protein
Day, I. N. M., & Thompson, R. J. (2009) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2009.10.020 · Cited by 271
“PARK2 or parkin is involved in protein degradation as a ubiquitin– protein ligase (Shimura et al., 2000, 2001) and causes autosomal recessive juvenile parkinsonism.”
Frosk, P., Weiler, T., Nylen, E., Sudha, T., Greenberg, C. R., Morgan, K., Fujiwara, T. M., & Wrogemann, K. (2002) · The American Journal of Human Genetics · doi:10.1086/339083 · Cited by 261
“Parkin, the product of PARK2, is known to be a RINGfinger–containing E3-Ub ligase (Shimura et al. 2000).”
BackgroundParkin Binds to α/β Tubulin and Increases their Ubiquitination and Degradation
Ren, Y., Zhao, J., & Feng, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-08-03316.2003 · Cited by 317
“…(Cleveland, 1989), the cellular mechanism for the degradation of tubulin in response to these neurotoxins may play a role in PD. Parkin, a gene linked to autosomal recessive juvenile PD (AR- JP) (Kitada et al., 1998) has been found to be a protein– ubiquitin E3 ligase (Shimura et al., 2000).”
BackgroundCD36 in chronic kidney disease: novel insights and therapeutic opportunities
Yang, X., Okamura, D. M., Lu, X., Chen, Y., Moorhead, J. F., Varghese, Z., & Ruan, X. Z. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2017.126 · Cited by 269
DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function
Hao, L.-Y., Giasson, B. I., & Bonini, N. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0911175107 · Cited by 270
“Parkin is an E3 ubiquitin ligase whose mutations account for themajority of autosomal recessive parkinsonism, and Parkinmay be important for mitophagy (13, 14).”
BackgroundParkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila
Cha, G., Kim, S., Park, J., Lee, E., Kim, M., Lee, S. B., Kim, J., Chung, J., & Cho, K. S. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0500346102 · Cited by 266
Zhang, X., Yuan, Y., Jiang, L., Zhang, J., Gao, J., Shen, Z., Zheng, Y., Deng, T., Yan, H., Li, W., et al. (2014) · Autophagy · doi:10.4161/auto.32136 · Cited by 259
Biomarker of Neuroinflammation in Parkinson’s Disease
Liu, T.-W., Chen, C., & Chang, K. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084148 · Cited by 272
The rotenone model of Parkinson's disease: genes, environment and mitochondria
Greenamyre, J. T., Betarbet, R. S., & Sherer, T. (2003) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(03)00023-3 · Cited by 265
“Recent work has shown that parkin is an E3 ubiquitin ligase [31,32], serving to link a polyubiquitin chain onto damaged or misfolded proteins, thereby targeting them for proteasomal degradation.”
BackgroundWei, H., Liu, L., & Chen, Q. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.03.013 · Cited by 266
Ved, R., Saha, S., Westlund, B., Perier, C., Griffin, L. B., Sluder, A. E., Hoener, M. C., Rodrigues, C. M. P., Alfonso, A., Steer, C. J., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505910200 · Cited by 262
Jiang, H., Ren, Y., Yuen, E. Y., Zhong, P., Ghaedi, M., Hu, Z., Azabdaftari, G., Nakaso, K., Yan, Z., & Feng, J. (2012) · Nature Communications · doi:10.1038/ncomms1669 · Cited by 254
Ubiquitination in postsynaptic function and plasticity
Mabb, A. M., & Ehlers, M. D. (2010) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100109-104129 · Cited by 255
“…parkin and the DUB UCH-L1 cause earlyonset familial forms of Parkinson’s disease (PD), which have the characteristic clinical features of tremor, rigidity, and bradykinesia as well as the classic histopathological loss of midbrain dopaminergic neurons (Leroy et al. 1998, Shimura et al. 2000).”
Mitochondrial dysfunction in the limelight of Parkinson's disease pathogenesis
Banerjee, R., Starkov, A. A., Beal, M. F., & Thomas, B. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.11.007 · Cited by 262
“Parkin is a RING finger containing protein and has been shown to function as an ubiquitin E3 ligase in vitro [162].”
BackgroundGenetic clues to the pathogenesis of Parkinson's disease
Vila, M., & Przedborski, S. (2004) · Nature Medicine · doi:10.1038/nm1068 · Cited by 259
Höglinger, G. U., Carrard, G., Michel, P. P., Medja, F., Lombès, A., Ruberg, M., Friguet, B., & Hirsch, É. C. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01952.x · Cited by 258
“Mutations in the gene encoding parkin, an E3-ubiquitinligase (Shimura et al. 2000), led to autosomal recessive juvenile parkinsonism (Kitada et al.”
BackgroundEndoplasmic reticulum stress response and neurodegeneration
Paschen, W., & Mengesdorf, T. (2005) · Cell Calcium · doi:10.1016/j.ceca.2005.06.019 · Cited by 252
Etiology of Parkinson’s disease
Schapira, A. H. V. (2006) · Neurology · doi:10.1212/wnl.66.10_suppl_4.s10 · Cited by 251
Molecular pathogenesis of Parkinson's disease
Gandhi, S., & Wood, N. W. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi308 · Cited by 251
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
