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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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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]
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“Parkin, in humans encoded by the PARK2 gene, is transcribed ubiquitously, and intracellular localization studies have reported the association of parkin and the endoplasmic reticulum, Golgi apparatus, synaptic vesicles and mitochondria [240,253,272].”
BackgroundKoyano, F., & Matsuda, N. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.02.009 · Cited by 46
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“Parkin, one of a number of E3 protein-ubiquitin ligases [11], mediates ubiquitination of itself, as well as an unusually large number of other protein substrates, including the α-SYN-interacting protein synphilin-1 (and other synaptic proteins), PaelR (parkin-associated endothelin-like receptor), cyclin E,”
BackgroundMorató, X., Luján, R., López‐Cano, M., Gandía, J., Štagljar, I., Watanabe, M., Cunha, R. A., Fernández‐Dueñas, V., & Ciruela, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-10147-x · Cited by 46
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“Parkin has been identified as an ubiquitin-protein ligase containing 465 amino acids (Shimura et al., 2000).”
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Shiiba, I., Takeda, K., Nagashima, S., Ito, N., Tokuyama, T., Yamashita, S., Kanki, T., Komatsu, T., Urano, Y., Fujikawa, Y., et al. (2021) · EMBO Reports · doi:10.15252/embr.201949097 · Cited by 45
“Mutations in PARK2 (Parkin), a ubiquitin E3 ligase, and PARK6 (PINK1), a ubiquitin kinase, are associated with the familial form of Parkinson’s disease (PD; Kitada et al , 1998; Shimura et al , 2000).”
Kajino, T., Omori, E., Ishii, S., Matsumoto, K., & Ninomiya‐Tsuji, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700875200 · Cited by 45
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“This protein was first reported to behave as an ubiquitin ligase (Shimura et al., 2000), and therefore, to be involved in proteasomemediated elimination of various substrates.”
BackgroundBrennan, L., Khoury, J., & Kantorow, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2016.09.020 · Cited by 45
The reversible effects of glial cell line–derived neurotrophic factor (GDNF) in the human brain
Ayanlaja, A. A., Zhang, B., Ji, G., Gao, Y., Wang, J., Kanwore, K., & Gao, D. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.07.005 · Cited by 44
Anderson, P. C., & Daggett, V. (2008) · Biochemistry · doi:10.1021/bi800677k · Cited by 45
“Genes of PARK1, PARK2 and PARK 5 encode α-synuclein (SNC A) (2), the E3 ubiquitinprotein ligase parkin (Parkin) (3,4) and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) (5), respectively.”
BackgroundAtypical Protein Kinase C in Neurodegenerative Disease II
Shao, C., Crary, J. F., Rao, C., Sacktor, T. C., & Mirra, S. S. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000218441.00040.82 · Cited by 45
“For example, ubiquitin is abundant in both tau- and >-synuclein-related inclusions (9), and malfunction of the ubiquitinYproteasome system has been implicated in inclusion formation, especially in the formation of Lewy bodies (10).”
BackgroundGenetic factors involved in the pathogenesis of Parkinson's disease
Lee, F. J. S., & Liu, F. (2008) · Brain Research Reviews · doi:10.1016/j.brainresrev.2008.02.001 · Cited by 43
Pael receptor is involved in dopamine metabolism in the nigrostriatal system
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The Genomic Structure and Promoter Region of the Human Parkin Gene
Asakawa, S., Tsunematsu, K., Takayanagi, A., Sasaki, T., Shimizu, A., Shintani, A., Kawasaki, K., Mungall, A. J. J., Beck, S., Minoshima, S., et al. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.5490 · Cited by 45
Self-citationThe emerging multifaceted role of PINK1 in cancer biology
Wang, M., Luan, S., Fan, X., Wang, J., Huang, J., Gao, X., & Han, D. (2022) · Cancer Science · doi:10.1111/cas.15568 · Cited by 49
Parkinsons Disease: Genetics and Beyond
Inamdar, N., Arulmozhi, D. K., Tandon, A., & Bodhankar, S. L. (2007) · Current Neuropharmacology · doi:10.2174/157015907780866893 · Cited by 46
Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration
Sul, J.-W., Park, M., Shin, J., Kim, Y., Yoo, S., Kong, Y., Kwon, K., Lee, Y., & Kim, E. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt006 · Cited by 44
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A copper hexacyanocobaltate nanocubes based dopamine sensor in the presence of ascorbic acid
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“Parkin and PINK1 mutations have been reported to be missense, nonsense or structural mutations (Shimura et al. 2000; Valente et al. 2004).”
BackgroundGenetic Mouse Models of Neurodegenerative Diseases
Trancikova, A. K., Ramonet, D., & Moore, D. J. (2011) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-384878-9.00012-1 · Cited by 47
Bandopadhyay, R., Kingsbury, A. E., Muqit, M. M. K., Harvey, K., Reid, A. R., Kilford, L., Engelender, S., Schlossmacher, M. G., Wood, N. W., Latchman, D. S., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.03.021 · Cited by 44
“Several recent reports have demonstrated the presence of parkin in LBs in sporadic PD (Murakami et al., 2004; Schlossmacher et al., 2002; Shimura et al., 2000) and in mitochondrial cybrids (Trimmer et al.”
BackgroundKo, L., Ko, H.-H. C., Lin, W.-L., Kulathingal, J. G., & Yen, S.-H. C. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31818c3618 · Cited by 44
“Recent identification of mutations in genes coding for parkin, an E3 ubiquitin ligase (47), and ubiquitin C-terminal hydrolases (UCHL-1) (48) has strengthened the link between ubiquitin-proteasome system dysfunction and PD pathogenesis (49).”
BackgroundLinkage Between the Proteasome Pathway and Neurodegenerative Diseases and Aging
Vigouroux, S., Briand, M., & Briand, Y. (2004) · Molecular Neurobiology · doi:10.1385/mn:30:2:201 · Cited by 43
“Parkin, the causal gene product for autosomal recessive juvenile Parkinsonism (AR-JP), acts as an E3 ubiquitin-protein ligase (123) and is contained in Lewy bodies (124).”
BackgroundMitochondrial ROS triggers mitophagy through activating the DNA damage response signaling pathway
Guo, Q., Wang, S.-S., Jiang, X.-Y., Xie, X.-C., Zou, Y. F., Liu, J., Guo, Y., Li, Y., Xm, L., Hao, S., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2502841122 · Cited by 48
“Mutations in PINK1 or Parkin that impair mitophagy have been linked to early - onset Parkinson’s disease (PD) ( 15 , 16 ).”
Loss-of-Function Rodent Models for Parkin and PINK1
Oliveras-Salvá, M., Rompuy, A. V., Heeman, B., den Haute, C. V., & Baekelandt, V. (2011) · Journal of Parkinson s Disease · doi:10.3233/jpd-2011-11041 · Cited by 44
“Parkin was very early on identified as an E3-ubiquitin ligase which led to the initial hypothesis that parkin played a role in proteasomal degradation of several target proteins, thereby reducing unfolded protein stress-induced cell death [9, 10].”
BackgroundProteomic Analysis of Cerebrospinal Fluid in Alzheimer's Disease: Wanted Dead or Alive
Galik-Olah, Z., Kalman, J. L., Tóth, M. E., Zvara, Á., Sántha, M., Ivitz, E., Janka, Z., & Pákáski, M. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-140141 · Cited by 43
Chew, K. C. M., Matsuda, N., Saisho, K., Lim, G. G. Y., Chai, C., Tan, H.-M., Tanaka, K., & Lim, K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019720 · Cited by 44
“Initial studies performed by three independent groups revealed that parkin functions as a ubiquitin ligase (E3) associated with the ubiquitin-proteasome system (UPS) [3,4,5], a major intracellular proteolytic machinery that destroys unwanted proteins.”
BackgroundSelf-citationValente, T. S., Baldi, F. S., Sant’Anna, A. C., de Albuquerque, L. G., & da Costa, M. J. R. P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0156956 · Cited by 44
Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury
Letsiou, E., Sammani, S., Wang, H., Belvitch, P. G., & Dudek, S. M. (2016) · Translational research · doi:10.1016/j.trsl.2016.09.002 · Cited by 43
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“The PINK1 protein encoded by PINK1 (PARK6) is a serine/threonine kinase, and the Parkin protein encoded by the Parkin (PARK2) gene is a RING finger containing the E3 ligase, which ubiquitinates many mitochondrial outer membrane proteins [75, 103].”
Zhang, X., Lin, C., Song, J., Chen, H., Chen, X., Ren, L., Zhou, Z., Pan, J., Yang, Z., Bao, W., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-1881-x · Cited by 43
RNA knockdown as a potential therapeutic strategy in Parkinson's disease
Manfredsson, F. P., Lewin, A. S., & Mandel, R. J. (2005) · Gene Therapy · doi:10.1038/sj.gt.3302669 · Cited by 43
Amine-related neurotoxins in Parkinson's disease
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Aguileta, M., Korać-Prlić, J., Durcan, T. M., Trempe, J., Haber, M., Gehring, K., Elsasser, S., Waidmann, O., Fon, E. A., & Husnjak, K. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.614925 · Cited by 43
“hRpn1 (409-551) 3-AT/ x-β-Gal prey -Trp/-Leu 3-AT parkin Ubl (2-76) bait B”
BackgroundParkinson's disease, proteins, and prions: Milestones
Olanow, C. W., & McNaught, K. S. P. (2011) · Movement Disorders · doi:10.1002/mds.23767 · Cited by 43
Liu, B., Traini, R., Killinger, B. A., Schneider, B. L., & Moszczyńska, A. (2013) · Experimental Neurology · doi:10.1016/j.expneurol.2013.01.001 · Cited by 42
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Parkin-mediated mitophagy and autophagy flux disruption in cellular models of MERRF syndrome
Paz, M. V., Povea-Cabello, S., Villalón-García, I., Álvarez-Córdoba, M., Suarez-Rivero, J. M., Talaverón-Rey, M., Jackson, S., Falcón‐Moya, R., Moreno, A. R., & Sánchez-Alcázar, J. A. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165726 · Cited by 42
Pessach, I. M., Walter, J. E., & Notarangelo, L. D. (2009) · Pediatric Research · doi:10.1203/pdr.0b013e31819dbe1e · Cited by 42
“PARK2 was discovered and characterized as culprit for early onset Parkinson’s disease (116).”
BackgroundBurchell, L., Chaugule, V. K., & Walden, H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0034748 · Cited by 42
“Parkin is a RING E3 ubiquitin ligase [1,2,3] which, in conjunction with a ubiquitin-activating enzyme (E1) and a ubiquitin-conjugating enzyme (E2), catalyses the attachment of ubiquitin to itself and to multiple putative substrates [4,5,6].”
BackgroundPARK6 is a common cause of familial parkinsonism
Valente, E. M., Brancati, F., Caputo, V., Graham, E. A., Davis, M. B., Ferraris, A., Breteler, M. M. B., Gasser, T., Bonifati, V., Bentivoglio, A. R., et al. (2002) · Neurological Sciences · doi:10.1007/s100720200097 · Cited by 42
“The Parkin gene codes for a protein with ubiquitin-ligase activity [4].”
Ikeuchi, K., Marusawa, H., Fujiwara, M., Matsumoto, Y. M., Endo, Y., Watanabe, T., Iwai, A., Sakai, Y., Takahashi, R., & Chiba, T. (2009) · International Journal of Cancer · doi:10.1002/ijc.24565 · Cited by 44
Self-citationSánchez, M. P., Gonzalo, I., Ávila, J., & de Yébenes, J. G. (2002) · Journal of Alzheimer s Disease · doi:10.3233/jad-2002-4506 · Cited by 42
“…Park-2 gene expressing parkin, an ubiquitin ligase component, E3, of the ubiquitin-proteasome dependent protein degradation pathway [9, 16–18 ,20 ,28 A decreased proteolysis of unphosphorylated tau in the tau-1 epitope, and an increase in tau phosphoryla-M tion were observed in the brain samples…”
Pankratz, N., & Foroud, T. (2004) · NeuroRx · doi:10.1602/neurorx.1.2.235 · Cited by 42
Parkin suppresses wild-type α-synuclein-induced toxicity in SHSY-5Y cells
Oluwatosin-Chigbu, Y., Robbins, A. K., Scott, C. W., Arriza, J. L., Reid, J. D., & Zysk, J. R. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.08.059 · Cited by 42
Scuderi, S., Cognata, V. L., Drago, F., Cavallaro, S., & D’Agata, V. (2014) · BioMed Research International · doi:10.1155/2014/690796 · Cited by 42
Expression profile of parkin isoforms in human gliomas
Maugeri, G., D’Amico, A. G., Magro, G. G., Salvatorelli, L., Barbagallo, G. M. V., Saccone, S., Drago, F., Cavallaro, S., & D’Agata, V. (2015) · International Journal of Oncology · doi:10.3892/ijo.2015.3105 · Cited by 41
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“E3 ubiquitin ligase that targets proteins for proteasomal degradation (107, 141, 183), pink 1 is a mitochondrialtargeted kinase (143, 168, 173), and UCH-L1 is an ubiquitin carboxy-terminal hydrolase.”
BackgroundModeling Parkinson’s Disease Using Patient-specific Induced Pluripotent Stem Cells
Li, H., Jiang, H., Zhang, B., & Feng, J. (2018) · Journal of Parkinson s Disease · doi:10.3233/jpd-181353 · Cited by 44
“The PARK2 gene encodes parkin [79], an E3 ligase [80] that ubiquitinates a variety of substrates [81].”
BackgroundThe Cast of Molecular Characters in Parkinson's Disease
LIM, K. L., Dawson, V. L., & Dawson, T. M. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb07465.x · Cited by 41
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“On the other hand, recent evidence suggests that endoplasmic reticulum (ER) stress contributes to rare familial PD (Imai et al., 2001; Shimura et al., 2000).”
Morphological and biochemical studies on aging and autophagy
Rezzani, R., Stacchiotti, A., & Rodella, L. F. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2011.09.001 · Cited by 40
Parkinson-Linked Genes and Toxins That Affect Neuronal Cell Death Through the Bcl-2 Family
Ethell, D. W., & Fei, Q. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2228 · Cited by 42
“Substrates for Parkin-mediated ubiquitylation include glycosylated (cid:2) - synuclein (91, 92), Pael-R, synphilin-1, CDCrel-1 and cyclinE.”
Molecular genetic pathways in Parkinson's disease: a review
Jain, S., Wood, N. W., & Healy, D. G. (2005) · Clinical Science · doi:10.1042/cs20050106 · Cited by 42
Parkin affects mitochondrial function and apoptosis in neuronal and myogenic cells
Kuroda, Y., Mitsui, T., Kunishige, M., & Matsumoto, T. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.06.201 · Cited by 41
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“As a negative control, we utilized Parkin with T240R mutation in the R1 domain or C431S mutation in the R2 domain, which are known to hinder interaction with the E2 enzyme or prevent activation of Parkin, respectively (9, 62).”
BackgroundMethodCo-chaperone CHIP Stabilizes Aggregate-prone Malin, a Ubiquitin Ligase Mutated in Lafora Disease
Rao, S. N. R., Sharma, J., Maity, R., & Jana, N. R. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.006312 · Cited by 40
PINK1 as a Molecular Checkpoint in the Maintenance of Mitochondrial Function and Integrity
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“Further, mutation of the Parkin gene, which encodes the E3 ligase Parkin [69], and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have been strongly associated with sporadic PD [70].”
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PINK1-Parkin signaling in Parkinson’s disease: Lessons from Drosophila
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The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins
Radzinski, M., Oppenheim, T., Metanis, N., & Reichmann, D. (2021) · Biomolecules · doi:10.3390/biom11030469 · Cited by 38
NK Lytic-Associated Molecule, Involved in NK Cytotoxic Function, Is an E3 Ligase
Fortier, J. M., & Kornbluth, J. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.11.6454 · Cited by 40
Caenorhabditis elegans as a Model System for Parkinson’s Disease
Schmidt, E., Seifert, M., & Baumeister, R. (2007) · Neurodegenerative Diseases · doi:10.1159/000101845 · Cited by 42
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Protein aggregation in Parkinson’s disease
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Novel peptides secreted from human neuroblastoma: useful clinical tools?
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Liu, M., Aneja, R., Sun, X., Xie, S., Wang, H., Wu, X., Dong, J., Li, M., Joshi, H. C., & Zhou, J. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806860200 · Cited by 42
Phosphorylation of HtrA2 by cyclin-dependent kinase-5 is important for mitochondrial function
Fitzgerald, J. C., Delgado-Camprubi, M., Dunn, L., Wu, H.-C., Ip, N. Y., Krüger, R., Martins, L. M., Wood, N. W., & Plun‐Favreau, H. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.90 · Cited by 40
“Contrary to PINK1 and HtrA2, Parkin does not include a MTS (33), yet parkin was recently shown to be recruited by PINK1 to depolarised mitochondria for initiating their clearance from the cell by autophagy (34-35).”
InfluentialDifferential expression and tissue distribution of parkin isoforms during mouse development
Huynh, D. P., Dy, M., Nguyen, D., Kiehl, T.-R., & Pulst, S. M. (2001) · Developmental Brain Research · doi:10.1016/s0165-3806(01)00234-6 · Cited by 40
The Cellular Protein Level of Parkin Is Regulated by Its Ubiquitin-like Domain
Finney, N., Walther, F., Mantel, P., Stauffer, D., Rovelli, G., & Dev, K. K. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300051200 · Cited by 40
Homozygous deletion mutation of the parkin gene in patients with atypical parkinsonism
Kuroda, Y. (2001) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.71.2.231 · Cited by 40
Mitochondrial dysfunction in Parkinson’s disease
Hattori, N., & Sato, S. (2024) · Journal of Neural Transmission · doi:10.1007/s00702-024-02863-2 · Cited by 41
“This is significant for understanding neurodegeneration in PD and other diseases related to abnormal protein ubiquitination (Shimura et al. 2000).”
Self-citationTransgenic animal models of neurodegeneration based on human genetic studies
Harvey, B. K., Richie, C. T., Hoffer, B. J., & Airavaara, M. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0476-6 · Cited by 38
“Parkin has an E3 ubiquitin-protein ligase activity (Shimura et al. 2000) and targets proteins for degradation by the proteosome (Zhang et al.”
The transcription factor X-box binding protein-1 in neurodegenerative diseases
Dunys, J., Duplan, E., & Checler, F. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-35 · Cited by 40
Functions and dysfunctions of the mammalian centrosome in health, disorders, disease, and aging
Schatten, H., & Sun, Q. (2018) · Histochemistry and Cell Biology · doi:10.1007/s00418-018-1698-1 · Cited by 38
El-Saiy, K. A., Sayed, R. H., El-Sahar, A. E., & Kandil, E. A. (2022) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2022.109841 · Cited by 38
Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases
Chen, Z., Geetha, T., & Babu, J. R. (2014) · Neurodegenerative Diseases · doi:10.1159/000367694 · Cited by 42
Harada, M., Kumemura, H., Omary, M. B., Kawaguchi, T., Maeyama, N., Hanada, S., Taniguchi, E., Koga, H., Suganuma, T., Ueno, T., et al. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00162-9 · Cited by 39
sgk1, a member of an RNA cluster associated with cell death in a model of Parkinson's disease
Stichel, C. C., Schoenebeck, B., Foguet, M., Siebertz, B., Bader, V., Zhu, X. R., & Lübbert, H. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.03859.x · Cited by 43
“…molecular genetics have furthered knowledge of the hereditary forms of PD (Ishikawa & Tsuji, 1996; Polymeropoulos et al., 1997; Hattori et al., 1998; Krüger et al., 1998; Shimura et al., 2000; Bonifati et al., 2002), the aetiology of the typical idiopathic (sporadic) form of PD is not yet clear.”
BackgroundTherapeutic strategies in Parkinson's disease: what we have learned from animal models
Valadas, J. S., Vos, M. H., & Verstreken, P. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12577 · Cited by 44
Gene-based Therapies in Parkinson's Disease
Allen, P. J., & Feigin, A. (2013) · Neurotherapeutics · doi:10.1007/s13311-013-0233-2 · Cited by 41
“Parkin is a ligase that polyubiquitinates proteins destined for degradation by the proteasome [69].”
BackgroundRompuy, A. V., Lobbestael, E., der Perren, A. V., den Haute, C. V., & Baekelandt, V. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000039 · Cited by 38
“The parkin protein consists of 465 amino acids and functions as an E3-ubiquitin ligase (8), which catalyzes the attachment of ubiquitin to substrate proteins, leading to their proteasomal degradation.”
BackgroundParkin reverses TDP ‐43‐induced cell death and failure of amino acid homeostasis
Hebron, M. L., Chen, W., Miessau, M., Lonskaya, I., & Moussa, C. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12630 · Cited by 38
“Parkin is an E3 ubiquitin ligase involved in protein degradation, while Park2 mutations result in loss of Parkin function, leading to autosomal recessive early onset Parkinson’s disease (Kitada et al. 1998; Lucking et al. 2000; Shimura et al. 2000; Cookson and Bandmann 2010).”
BackgroundRole of E3 ubiquitin ligases in lung cancer
Snoek, B. C. (2013) · World Journal of Clinical Oncology · doi:10.5306/wjco.v4.i3.58 · Cited by 38
Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis
Gong, Y., Schumacher, S. E., Wu, W., Tang, F., Beroukhim, R., & Chan, T. A.-T. (2016) · Neoplasia · doi:10.1016/j.neo.2016.12.006 · Cited by 38
“The PARK2 gene encodes a ubiquitin E3 ligase that can target proteins for degradation through the ubiquitin-proteasome system [8,9].”
BackgroundShared genes between Alzheimer’s disease and ischemic stroke
Wei, C., Cui, P., Li, H., Lang, W., Liu, G., & Ma, X. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13117 · Cited by 38
Huang, E., Huang, H., Guan, T., Liu, C., Qu, D., Xu, Y., Yang, J., Yan, L., Xiong, Y., Liang, T. B., et al. (2019) · Toxicology Letters · doi:10.1016/j.toxlet.2019.05.003 · Cited by 38
Phosphorylation of Rab GTPases in the regulation of membrane trafficking
Waschbüsch, D., & Khan, A. R. (2020) · Traffic · doi:10.1111/tra.12765 · Cited by 40
“TBK1 phosphorylation is dependent upon Parkin, an E3 ubiquitin ligase that is associated with inherited Parkinson disease.(29,30) TBK1 phosphorylation of Rab7 is associated with a decrease in recruitment of ATG9-positive vesicles to damaged mitochondria and a defect in mitophagy.”
BackgroundSynphilin‐1 degradation by the ubiquitin‐proteasome pathway and effects on cell survival
Lee, G., Junn, E., Tanaka, M., Kim, Y. M., Lee, S. S., & Mouradian, M. M. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.01136.x · Cited by 38
“Parkin itself, which when mutated results in autosomal recessive PD (Kitada et al. 1998), is an E3 ubiquitin ligase (Shimura et al. 2000; Zhang et al. 2000).”
BackgroundImpaired Neurotransmitter Release in Alzheimer’s and Parkinson’s Diseases
Shen, J. (2010) · Neurodegenerative Diseases · doi:10.1159/000285511 · Cited by 38
Kubo, S., Hattori, N., & Mizuno, Y. (2006) · Movement Disorders · doi:10.1002/mds.20841 · Cited by 39
Self-citationParkin and synphilin-1 isoform expression changes in Lewy body diseases
Humbert, J., Beyer, K., Carrato, C., Mate, J. L., Ferrer, I., & Ariza, A. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.03.007 · Cited by 38
“Parkin coordinates the transfer of ubiquitin to specific substrate proteins and thereby targets them for proteasome degradation (Shimura et al., 2000).”
BackgroundBiswas, A., Gupta, A., Naiya, T., Das, G., Neogi, R., Datta, S., Mukherjee, S., Das, S. K., Ray, K., & Ray, J. (2006) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2006.04.005 · Cited by 38
“Parkin is an E3-ligase, catalyzing the addition of ubiquitin to specific substrates that targets them for degradation through ubiquitin–proteasome systems [9].”
BackgroundParkin gene causing benign autosomal recessive juvenile parkinsonism
Nisipeanu, P., Inzelberg, R., Mouch, S. A., Carasso, R., Blumen, S. C., Zhang, J., Matsumine, H., Hattori, N., & Mizuno, Y. (2001) · Neurology · doi:10.1212/wnl.56.11.1573 · Cited by 38
Self-citationl-DOPA Impairs Proteasome Activity in Parkinsonism through D1Dopamine Receptor
Berthet, A., Bézard, E., Porras, G., Fasano, S., Barroso‐Chinea, P., Dehay, B., Martínez, A., Thiolat, M.-L., Nosten‐Bertrand, M., Giros, B., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.1541-11.2012 · Cited by 40
“Since parkin is an E3 ubiquitin-protein ligase (Shimura et al., 2000), its functional loss would precede a putative dopaminedependent impairment in proteasome activity in striatal neurons, offering an explanation for the early appearance of LID in these patients.”
BackgroundPost-translational modifications in neurodegeneration
Didonna, A., & Benetti, F. (2015) · AIMS Biophysics · doi:10.3934/biophy.2016.1.27 · Cited by 36
“Protein Biological function Effect of S-nitrosylation Parkin E3 ubiquitin ligase participating in the ubiquitin-proteasome system [156] Altered E3 ligase activity and protein misfolding [149]”
MicroRNAs: Possible role in pathogenesis of Parkinson’s disease
Filatova, E. V., Alieva, A. K., Shadrina, M. I., & Slominsky, P. A. (2012) · Biochemistry (Moscow) · doi:10.1134/s0006297912080020 · Cited by 39
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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