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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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Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
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Self-citationAlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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Cellular strategies for making monoubiquitin signals
Ramanathan, H. N., & Ye, Y. (2011) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2011.620943 · Cited by 59
“Parkin is a RING E3 ubiquitin ligase (Shimura et al., 2000) and mutations in Parkin have been linked to the onset of Parkinson’s disease (Kitada et al., 1998).”
BackgroundWang, H., Imai, Y., Inoue, H., Kataoka, A., Iita, S., Nukina, N., & Takahashi, R. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05607.x · Cited by 58
“…ligase (E3) and loss of E3 activity causes AR-JP, suggesting that substrate(s) of parkin, which cannot be properly degraded and accumulates in AR-JP patients, may cause dysfunction and eventually the death of susceptible neurons (Imai et al. 2000; Shimura et al. 2000; von Coelln et al. 2004a).”
BackgroundLang‐Mladek, C., Guger, K., & Hauser, M. (2003) · PLANT PHYSIOLOGY · doi:10.1104/pp.012781 · Cited by 57
“Disease-associated mutations within the RING1 of the R-IBR-R domain destroy E3 activity (Shimura et al., 2000).”
BackgroundPost translational modification of Parkin
Chakraborty, J., Basso, V., & Ziviani, E. (2017) · Biology Direct · doi:10.1186/s13062-017-0176-3 · Cited by 58
Metabolomics‐based identification of metabolic alterations in PARK2
Okuzumi, A., Hatano, T., Ueno, S., Ogawa, T., Saiki, S., Mori, A., Koinuma, T., Oji, Y., Ishikawa, K., Fujimaki, M., et al. (2019) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.724 · Cited by 55
Self-citationHeterozygote carriers for CNVs inPARK2are at increased risk of Parkinson's disease
Huttenlocher, J., Stefánsson, H., Steinberg, S., Helgadottir, H. T., Sveinbjörnsdóttir, S., Rieß, O., Bauer, P. O., & Stefánsson, K. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv277 · Cited by 57
“ligase (6), are responsible for 50% of familial early onset PD (7,8).”
BackgroundHwang, G., Furuchi, T., & Naganuma, A. (2002) · The FASEB Journal · doi:10.1096/fj.01-0899fje · Cited by 57
RING Finger Ubiquitin-Protein Isopeptide Ligase Nrdp1/FLRF Regulates Parkin Stability and Activity
Zhong, L., Tan, Y., Zhou, A., Yu, Q., & Zhou, J. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m408955200 · Cited by 57
PINK, PANK, or PARK? A clinicians' guide to familial parkinsonism
Healy, D. G., Abou‐Sleiman, P. M., & Wood, N. W. (2004) · The Lancet Neurology · doi:10.1016/s1474-4422(04)00905-6 · Cited by 57
Mitochondrial dynamics and neuronal fate in Parkinson's disease
Santos, D., & Cardoso, S. M. (2012) · Mitochondrion · doi:10.1016/j.mito.2012.05.002 · Cited by 60
Intertwined Relationship of Mitochondrial Metabolism, Gut Microbiome and Exercise Potential
Imdad, S., Lim, W., Kim, J., & Kang, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052679 · Cited by 60
“H2S Cysteine catabolic bacteria: Fusobacterium, Clostridium, Escherichia, Salmonella, Klebsiella, Streptococcus, Desulfovibrio, and Enterobacter [98] Sulfate reduction operon (dsrAB), cysteine desulfhydrase (dcyD), yhaOM operon, methionine gamma-lyase (mgl), cysteine aminotransferase + 3-mercaptopyruvate sulfurtransfe…”
BackgroundUse of viral vectors to create animal models for Parkinson's disease
Löw, K., & Aebischer, P. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.038 · Cited by 60
Wilkaniec, A., Lenkiewicz, A. M., Czapski, G. A., Jęśko, H. M., Hilgier, W., Brodzik, R., Gąssowska-Dobrowolska, M., Culmsee, C., & Adamczyk, A. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1082-0 · Cited by 56
Rajagopalan, S., & Andersen, J. K. (2001) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(01)00283-4 · Cited by 56
Parkin regulates kainate receptors by interacting with the GluK2 subunit
Maraschi, A., Ciammola, A., Folci, A., Sassone, F., Ronzitti, G., Cappelletti, G., Silani, V., Sato, S., Hattori, N., Mazzanti, M., et al. (2014) · Nature Communications · doi:10.1038/ncomms6182 · Cited by 55
Self-citationDopamine receptor mapping with PET imaging in Parkinson’s disease
Niccolini, F., Su, P., & Politis, M. (2014) · Journal of Neurology · doi:10.1007/s00415-014-7302-2 · Cited by 54
“The parkin gene on chromosome 6q25-27 encodes a ubiquitin ligase enzyme involved in protein degradation, where mutations (autosomal recessive) presumably lead to aberrant accumulation of cell proteins, resulting in neuronal dysfunction and death [52].”
BackgroundOxidative Modification and Its Implications for the Neurodegeneration of Parkinson’s Disease
Zhao, J., Yu, S., Zheng, Y., Yang, H., & Zhang, J. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-9743-3 · Cited by 58
Twenty years since the discovery of the parkin gene
Hattori, N., & Mizuno, Y. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1742-7 · Cited by 55
Self-citationAberrant Folding of Pathogenic Parkin Mutants
Schlehe, J. S., Lutz, A. K., Pilsl, A., Lämmermann, K., Grgur, K., Henn, I. H., Tatzelt, J., & Winklhofer, K. F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707494200 · Cited by 55
Coding Polymorphisms in the Parkin Gene and Susceptibility to Parkinson Disease
Lücking, C.-B., Chesneau, V., Lohmann, E., Verpillat, P., Dulac, C., Bonnet, A.-M., Gasparini, F., Agid, Y., Dürr, A., & Brice, A. (2003) · Archives of Neurology · doi:10.1001/archneur.60.9.1253 · Cited by 55
“Because they are both located in the RINGIBR-RING domain of parkin, one might speculate that they could affect the binding of substrates or E2 proteinubiquitin–conjugating enzymes (UbcH7 and 8).(14,15) In addition, Asp394 might create a caspase cleavage site.”
BackgroundKhan, M. M., Nomura, T., Chiba, T., Tanaka, K., Yoshida, H., Mori, K., & Ishii, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312121200 · Cited by 55
Self-citationparkin mutation analysis in clinic patients with early‐onset Parkinson's disease
Poorkaj, P., Nutt, J. G., James, D., Gancher, S., Bird, T. D., Steinbart, E. J., Schellenberg, G. D., & Payami, H. (2004) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.30157 · Cited by 55
“The protein product, Parkin, functions as an ubiquitin E3 ligase in the proteosome degradation pathway [Shimura et al., 2000].”
BackgroundCombined kinase inhibition modulates parkin inactivation
de la Torre, E. R., Luzón-Toro, B., Forte‐Lago, I., Mínguez‐Castellanos, A., Ferrer, I., & Hilfiker, S. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn407 · Cited by 55
“Parkin functions as an E3 ubiquitin ligase (13), and inactivation of its catalytic activity may lead to dopaminergic cell death due to the accumulation of toxic substrate protein(s).”
BackgroundRoles of LIM kinases in central nervous system function and dysfunction
Cuberos, H., Vallée, B., Vourc'h, P., Tastet, J., Andres, C. R., & Bénédetti, H. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.10.032 · Cited by 54
Transgenic rodent models of Parkinson’s disease
Harvey, B. K., Wang, Y., & Hoffer, B. J. (2009) · Acta neurochirurgica. Supplementum · doi:10.1007/978-3-211-78205-7_15 · Cited by 55
Aggregopathy in Neurodegenerative Diseases: Mechanisms and Therapeutic Implication
Dohm, C. P., Kermer, P., & Bähr, M. (2008) · Neurodegenerative Diseases · doi:10.1159/000119459 · Cited by 56
Parkin and Endoplasmic Reticulum Stress
Takahashi, R., Imai, Y., Hattori, N., & Mizuno, Y. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb07467.x · Cited by 54
Self-citationAstrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases
Martín-Jiménez, C., García-Vega, Á. S., Cabezas, R., Aliev, G., Echeverrı́a, V., González, J., & Barreto, G. E. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.001 · Cited by 56
“Most studies on ER stress in PD are associated with Parkin and a-synuclein; while the first protein is a ubiquitin-protein ligase defective in familial PD, the second one is a protein found in Lewy bodies (Shimura et al., 2000; Spillantini et al., 1997).”
BackgroundInfluentialMendelian neurodegenerative disease genes involved in autophagy
Stamatakou, E., Wróbel, L., Hill, S. M., Puri, C., Son, S. M., Fujimaki, M., Zhu, Y., Siddiqi, F. H., Fernandez-Estévez, M., Manni, M. M., et al. (2020) · Cell Discovery · doi:10.1038/s41421-020-0158-y · Cited by 52
Hishikawa, N., Niwa, J.-I., Doyu, M., Ito, T., Ishigaki, S., Hashizume, Y., & Sobue, G. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63688-7 · Cited by 54
Liu, X., Hebron, M. L., Mulki, S., Wang, C., Lekah, E., Ferrante, D., Shi, W., Kurd-Misto, B. T., & Moussa, C. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190635 · Cited by 53
Involvement of Mitochondria in Parkinson’s Disease
Choong, C., & Mochizuki, H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242317027 · Cited by 58
“Parkin, an E3 ubiquitin ligase, ubiquitinates and targets protein substrates for degradation via the ubiquitin proteasome system [33].”
BackgroundShotgun Proteomics in Neuroscience
Liao, L., McClatchy, D. B., & Yates, J. R. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.011 · Cited by 53
“Finally, phosphorylation, ubiquitination, and other modifications have been implicated in many neurological disorders, including Alzheimer's, Parkinson's, and Huntington's diseases (Geschwind, 2003; Chen and Feany, 2005; Shimura et al., 2000; Valera et al., 2005), and they have become the target of many proteomic anal…”
Are heat shock proteins therapeutic target for Parkinson's disease?
Luo, G., Chen, S., & Le, W.-D. (2007) · International Journal of Biological Sciences · doi:10.7150/ijbs.3.20 · Cited by 53
“It is believed that HSPs, UPS, mitochondria and other organelles may work coordinately to keep the cell in a stable and well-operated state.”
BackgroundInfluentialImaging of dopaminergic dysfunction with [ 123 I]FP-CIT SPECT in early-onset parkin disease
Varrone, A., Pellecchia, M. T., Amboni, M., Sansone, V., Salvatore, E., Ghezzi, D., Garavaglia, B., Brice, A., Brunetti, A., Bonavita, V., et al. (2004) · Neurology · doi:10.1212/01.wnl.0000145765.19094.94 · Cited by 53
Lopes, J. P., Morató, X., de Souza, C. A., Pinhal, C. M., Machado, N. J., Canas, P. M., Silva, H. B. L., Štagljar, I., Gandía, J., Fernández‐Dueñas, V., et al. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13109 · Cited by 53
“The loss of function of parkin is characteristic of autosomal recessive juvenile Parkinson’s disease (PD) (Kitada et al. 1998), where a toxic accumulation of parkin substrates (i.e., GPR37) occurs (Shimura et al. 2000; Sriram et al. 2005).”
BackgroundSekine, S. (2019) · The Journal of Biochemistry · doi:10.1093/jb/mvz069 · Cited by 53
New parkin mutations and atypical phenotypes in families with autosomal recessive parkinsonism
Rawal, N., Periquet, M., Lohmann, E., Lücking, C. B., Teive, H. A. G., Ambrosio, G., Raskin, S., Lincoln, S. J., Hattori, N., Guimaraes, J., et al. (2003) · Neurology · doi:10.1212/01.wnl.0000056167.89221.be · Cited by 53
Self-citationA mutational atlas for Parkin proteostasis
Clausen, L., Voutsinos, V., Cagiada, M., Johansson, K. E., Grønbæk-Thygesen, M., Nariya, S., Powell, R. L., Have, M. K. N., Oestergaard, V. H., Stein, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45829-4 · Cited by 51
“The PRKN gene encodes the E3 ubiquitin-protein ligase, Parkin (Shimura et al., 2000), which catalyzes protein ubiquitination and is required for mitophagy of damaged mitochondria (Panicker et al.”
Cartelli, D., Goldwurm, S., Casagrande, F., Pezzoli, G., & Cappelletti, G. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037467 · Cited by 52
“Although parkin and LRRK2 seem to act on different physiological processes, being parkin an E3 ligase catalyzing the addition of ubiquitin to target proteins [3] and LRRK2 a multi-domain protein involved in the regulation of neuronal process elongation [4], their actions converge on microtubules (MTs) [5,6].”
BackgroundParkin mutations in familial and sporadic Parkinson's disease among Indians
Chaudhary, S., Behari, M., Dihana, M., Swaminath, P. V., Govindappa, S. T., Jayaram, S., Goyal, V., Maitra, A., Muthane, U. B., Juyal, R. C., et al. (2006) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2005.12.004 · Cited by 52
“Recently, it has been shown to be an E3 ligase, and suggested to play a major role in the Ubiquitin Proteosome degradation pathway [30].”
BackgroundThe Role of α-Synuclein Assembly and Metabolism in the Pathogenesis of Lewy Body Disease
Hashimoto, M., Kawahara, K., Bar‐On, P., Rockenstein, E. M., Crews, L. A., & Masliah, E. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:3:343 · Cited by 53
Disease-modifying drugs and Parkinson's disease
Allain, H., Bentué‐Ferrer, D., & Akwa, Y. (2007) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2007.10.003 · Cited by 52
Akhtar, M. W., Sunico, C. R., Nakamura, T., & Lipton, S. A. (2012) · International Journal of Cell Biology · doi:10.1155/2012/463756 · Cited by 55
“As an example, mutations in the parkin gene are known to cause many cases of the autosomal-recessive juvenile Parkinsonism and some rare cases of adult-onset PD [56–59].”
Parkin Protects against Oxygen‐Glucose Deprivation/Reperfusion Insult by Promoting Drp1 Degradation
Tang, J., Hu, Z., Tan, J., Yang, S., & Zeng, L. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/8474303 · Cited by 51
“Parkin is a widely expressed 465 amino acid protein that possesses E3 ubiquitin-protein ligase activity [16].”
BackgroundLipid profiling of parkin‐mutant human skin fibroblasts
Lobasso, S., Tanzarella, P., Vergara, D., Maffia, M., Cocco, T., & Corcelli, A. (2017) · Journal of Cellular Physiology · doi:10.1002/jcp.25815 · Cited by 54
“PARK-2 gene encodes parkin, a protein that belongs to the ring between ring (RBR) fingers class of E3 ubiquitin ligases (Kitada et al., 1998; Shimura et al., 2000).”
BackgroundActivating Autophagy as a Therapeutic Strategy for Parkinson’s Disease
Fowler, A. J., & Moussa, C. (2018) · CNS Drugs · doi:10.1007/s40263-018-0497-5 · Cited by 51
Machine learning discriminates a movement disorder in a zebrafish model of Parkinson's disease
Hughes, G. L., Lones, M. A., Bedder, M., Currie, P. D., Smith, S. L., & Pownall, M. E. (2020) · Disease Models & Mechanisms · doi:10.1242/dmm.045815 · Cited by 52
“Studying the genes disrupted in patients with inherited forms of PD has been instrumental for progress in understanding the molecular basis of the disease (Clark et al., 2006; Clements et al., 2006; Shimura et al., 2000).”
BackgroundGenetics of Parkinson’s disease and parkinsonism
Douglas, M. R., Lewthwaite, A. J., & Nicholl, D. J. (2007) · Expert Review of Neurotherapeutics · doi:10.1586/14737175.7.6.657 · Cited by 53
Parkin interacts with the proteasome subunit α4
Dächsel, J. C., Lücking, C. B., Deeg, S., Schultz, E., Lalowski, M. M., Casademunt, E., Corti, O., Hampe, C., Patenge, N., Vaupel, K., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.06.003 · Cited by 52
“[4], and conjugates activated ubiquitin to proteins for further degradation by the 26S proteasome.”
BackgroundMutant α-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease
Haywood, A. F. M., & Staveley, B. E. (2006) · Genome · doi:10.1139/g06-011 · Cited by 53
Early-Onset Parkinson’s Disease: Creating the Right Environment for a Genetic Disorder
Kolicheski, A., Turcano, P., Tamvaka, N., McLean, P. J., Springer, W., Savica, R., & Ross, O. A. (2022) · Journal of Parkinson s Disease · doi:10.3233/jpd-223380 · Cited by 58
“PRKN encodes for PARKIN, which was first shown to function in the Ub-proteasome degradation pathway in the early 2000 s [94, 95].”
BackgroundWalker, L. C., & LeVine, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00160-3 · Cited by 51
Scheuerle, A. E., & Wilson, K. (2011) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.31176 · Cited by 50
“This accumulation ispresumed to cause neural cell death and decreased protection against stressinduced apoptosis [Shimura et al., 2000; Imai et al., 2002; Jiang et al., 2004].”
BackgroundCD 4+ T cells in the pathobiology of neurodegenerative disorders
Huang, X., Reynolds, A. D., Mosley, R. L., & Gendelman, H. E. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.04.006 · Cited by 51
The receptor proteins: pivotal roles in selective autophagy
Xu, Z., Yang, L., Xu, S., Zhang, Z., & Cao, Y. (2015) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gmv055 · Cited by 57
“TRIM5α is one member of the TRIM family and consists of RING, B-box 2, CC, and SPRY domains (Fig.”
BackgroundInfluentialUllah, K., Zubia, E., Narayan, M., Yang, J., & Xu, G. (2018) · FEBS Journal · doi:10.1111/febs.14708 · Cited by 53
Parkin's Substrates and the Pathways Leading to Neuronal Damage
Cookson, M. (2003) · NeuroMolecular Medicine · doi:10.1385/nmm:3:1:1 · Cited by 50
“This is similar to other RING type E3 ligases, such as Cbl, which interacts with UbcH7 where there is crystallographic information (Zheng et al., 2000).”
InfluentialGender differences and estrogen effects in parkin null mice
Rodríguez‐Navarro, J. A., Solano, R. M., Casarejos, M. J., Gómez, A., Perucho, J., de Yébenes, J. G., & Mena, M. A. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05569.x · Cited by 51
Paschen, W., & Mengesdorf, T. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.05.008 · Cited by 52
PINK1: A Bridge between Mitochondria and Parkinson’s Disease
Gonçalves, F. B., & Morais, V. A. (2021) · Life · doi:10.3390/life11050371 · Cited by 52
“Mutations in several of these PARK genes also cause mitochondrial dysfunctions, namely PINK1 (PARK6) 5 and Parkin (PARK2) [60,61].”
BackgroundSegawa, M. (2011) · Handbook of clinical neurology · doi:10.1016/b978-0-444-52014-2.00039-2 · Cited by 50
Protein stability and aggregation in Parkinson's disease
Robinson, P. A. (2008) · Biochemical Journal · doi:10.1042/bj20080295 · Cited by 50
Eckermann, K. (2013) · NeuroMolecular Medicine · doi:10.1007/s12017-013-8259-5 · Cited by 52
Tan, N. G. S., Ardley, H. C., Scott, G. B., Rose, S. A., Markham, A. F., & Robinson, P. A. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)01235-3 · Cited by 50
Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson’s disease
Romaní-Aumedes, J., Canal, M., Martín‐Flores, N., Sun, X., Pérez-Fernández, V., Wewering, S., Fernández‐Santiago, R., Ezquerra, M., Pont‐Sunyer, C., Lafuente, A., et al. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.333 · Cited by 55
“These PARK2 mutations are linked to the appearance of an autosomal recessive form of juvenile parkinsonism (AR-JP).(5,6)”
Witte, M. E., Bol, J. G. J. M., Gerritsen, W. H., van der Valk, P., Drukarch, B., van Horssen, J., & Wilhelmus, M. M. M. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.08.009 · Cited by 53
Hwang, C. J., Kim, Y., Son, D. J., Park, M. H., Choi, D., Park, P., Hellström, M., Han, S., Oh, K., Park, E., et al. (2016) · Redox Biology · doi:10.1016/j.redox.2016.12.008 · Cited by 50
Parkin absence accelerates microtubule aging in dopaminergic neurons
Cartelli, D., Amadeo, A., Calogero, A. M., Casagrande, F., Gregorio, C. D., Gioria, M., Kuzumaki, N., Costa, I., Sassone, J., Ciammola, A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.010 · Cited by 50
Self-citationPringa, E., Martínez-Noël, G., Müller, U., & Harbers, K. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m100192200 · Cited by 49
Intracellular dopamine oxidation mediates rotenone-induced apoptosis in PC12 cells
Liu, H., Zhu, X., & En-qi, W. (2005) · Acta Pharmacologica Sinica · doi:10.1111/j.1745-7254.2005.00003.x · Cited by 50
Inden, M., Kondo, J., Kitamura, Y., Takata, K., Nishimura, K., Taniguchi, T., Sawada, H., & Shimohama, S. (2005) · Journal of Pharmacological Sciences · doi:10.1254/jphs.fp0040525 · Cited by 50
Yasuda, T., & Mochizuki, H. (2010) · APOPTOSIS · doi:10.1007/s10495-010-0486-8 · Cited by 51
“Parkin mainly serves as an E3 ubiquitin ligase, catalyzing K48-linked polyubiquitination for proteasomal degradation of substrates [17, 130].”
Hargus, G., Ehrlich, M., Hallmann, A.-L., & Kuhlmann, T. (2013) · Acta Neuropathologica · doi:10.1007/s00401-013-1222-6 · Cited by 54
“PINK1 encodes a kinase localized at the outer mitochondrial membrane, while PAR‐ KIN encodes an e3 ubiquitin ligase found in the cytosol [119, 161, 188].”
BackgroundParkin-dependent regulation of the MCU complex component MICU1
Matteucci, A., Patrón, M., Reane, D. V., Gastaldello, S., Amoroso, S., Rizzuto, R., Brini, M., Raffaello, A., & Calí, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-32551-7 · Cited by 50
Srivastav, S., Anand, B. G., Fatima, M., Prajapati, K. P., Yadav, S. S., Kar, K., & Mondal, A. C. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00366 · Cited by 49
Targeting ASK1 in ER stress-related neurodegenerative diseases
Homma, K., Katagiri, K., Nishitoh, H., & Ichijo, H. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220902980249 · Cited by 49
“Hereditary mutations in the ER-associated ubiquitin E3 ligase Parkin gene are found in patients with familial PD [86,87].”
BackgroundParkinson's disease: the genetics of a heterogeneous disorder
Gosal, D. Y., Ross, O. A., & Toft, M. (2006) · European Journal of Neurology · doi:10.1111/j.1468-1331.2006.01336.x · Cited by 49
“the transfer of activated ubiquitin molecules to a substrate [93].”
BackgroundChasing genes in Alzheimer?s and Parkinson?s disease
Bertoli‐Avella, A. M., Oostra, B. A., & Heutink, P. (2004) · Human Genetics · doi:10.1007/s00439-004-1097-7 · Cited by 48
Sekiyama, K., Sugama, S., Fujita, M., Sekigawa, A., Takamatsu, Y., Waragai, M., Takenouchi, T., & Hashimoto, M. (2012) · Parkinson s Disease · doi:10.1155/2012/271732 · Cited by 51
“Parkin, mutations of which are present in at least 50% of patients with autosomal recessive juvenile parkinsonism [29], is a ubiquitin E3 ligase [30].”
BackgroundAdvances with microRNAs in Parkinson’s disease research
Yuan, W., Ma, L., Wei, L. L., Wu, F., Hu, Z., & Liu, Z. (2013) · Drug Design Development and Therapy · doi:10.2147/dddt.s48500 · Cited by 51
“2-27 will cause autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of PD. 53 It has been reported that parkin participates in the proteasome-mediated degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7.”
InfluentialSakamoto, M., Uchihara, T., Hayashi, M., Nakamura, A., Kikuchi, E., Mizutani, T., Mizusawa, H., & Hirai, S. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7961 · Cited by 47
Neuromelanin inhibits enzymatic activity of 26S proteasome in human dopaminergic SH-SY5Y cells
Shamoto‐Nagai, M., Maruyama, W., Akao, Y., Osawa, T., Tribl, F., Gerlach, M., Zucca, F. A., Zecca, L., Riederer, P. F., & Naoi, M. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0211-2 · Cited by 48
Molecular analysis of the parkin gene in South African patients diagnosed with Parkinson's disease
Bardien, S., Keyser, R. J., Yako, Y. Y., Lombard, D., & Carr, J. A. (2008) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2008.04.005 · Cited by 48
The aetiology of idiopathic Parkinson's disease.
Ramsden, D. B., Parsons, R. B., Ho, S. L., & Waring, R. H. (2001) · Europe PMC (PubMed Central) · doi:10.1136/mp.54.6.369 · Cited by 48
Molecular Findings in Familial Parkinson Disease in Spain
Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jiménez‐Jiménez, F. J., Berciano, J., del Ser, T., Jiménez, A., Ruiz, P., & de Yébenes, J. G. (2002) · Archives of Neurology · doi:10.1001/archneur.59.6.966 · Cited by 48
“In its COOHterminus there are 2 RING-finger motifs and an IBR (in between RING fingers), organized as a RING-IBR-RING domain.(8,9) Thus, patients with parkin mutations could have an abnormal ubiquitination pathway.”
BackgroundHorowitz, J. M., Vernace, V. A., Myers, J. M., Stachowiak, M. K., Hanlon, D., Fraley, G. S., & Torres, G. (2001) · Journal of Chemical Neuroanatomy · doi:10.1016/s0891-0618(00)00111-3 · Cited by 48
The neurological mutant quaking viable is Parkin deficient
Lorenzetti, D., Antalffy, B. A., Vogel, H. S., Noveroske, J. K., Armstrong, D. L., & Justice, M. J. (2004) · Mammalian Genome · doi:10.1007/s00335-003-2333-5 · Cited by 48
“…pathway, which eventually leads to the degradation of polyubiquitinated substrates by the proteasome complex 210 DOI: 10.1007/s00335-003-2333-5 • Volume 15, 210–217 (2004) • Springer-Verlag New York, Inc. 2004 Correspondence to: M. Justice; E-mail: mjustice@bcm.tmc.edu (Shimura et al. 2000).”
BackgroundInfluentialBryan, L. L. K., CLYNES, M. M., & Meleady, P. (2021) · Biotechnology Advances · doi:10.1016/j.biotechadv.2021.107757 · Cited by 50
Mitochondrial protein dysfunction in pathogenesis of neurological diseases
Wang, L., Yang, Z., He, X., Pu, S., Yang, C., Wu, Q., Zhou, Z., Cen, X., & Zhao, H. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.974480 · Cited by 48
“Protein structural analysis shows that Parkin protein consists of a ubiquitin-like (Ubl) domain at the amino terminus and four RING domains: RING0, RING1, IBR, and RING2 (Shimura et al., 2000; Hristova et al., 2009; Trempe et al., 2013).”
BackgroundMetabolism of amyloid β peptide and pathogenesis of Alzheimer’s disease
Saido, T. C. (2013) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.89.321 · Cited by 47
Reversible generalized dystonia and encephalopathy from thiamine transporter 2 deficiency
Serrano, M., Rebollo, M., Depienne, C., Rastetter, A., Fernández‐Álvarez, E., Muchart, J., Martorell, L., Artuch, R., Obeso, J. A., & Pérez‐Dueñas, B. (2012) · Movement Disorders · doi:10.1002/mds.25008 · Cited by 47
“dren with progressive cerebral atrophy accompanied by lesions of the basal ganglia and thalamus.(5)”
BackgroundFunctions and characteristics of PINK1 and Parkin in cancer
Matsuda, S. (2015) · Frontiers in bioscience · doi:10.2741/4321 · Cited by 47
Altered α‐synuclein, parkin, and synphilin isoform levels in multiple system atrophy brains
Brudek, T., Winge, K., Rasmussen, N. B., Bahl, J. M. C., Tanassi, J. T., Agander, T. K., Hyde, T. M., & Pakkenberg, B. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.13392 · Cited by 48
“Parkin is widely expressed across the CNS and is a component of the E3 ubiquitin ligase complex that mediates the targeting of proteins for degradation (Imai et al. 2000; Shimura et al. 2000; Cookson 2003).”
BackgroundSmith, N. J. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00275 · Cited by 47
“It is specifically through the loss of E3 ubiquitin ligase activity that parkin mutations are pathogenic (Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000), leading to the accumulation of a number of substrates including GPR37 (Imai et al., 2001).”
BackgroundMitochondrial quality surveillance: mitophagy in cardiovascular health and disease
Diao, R. Y., & Gustafsson, Å. B. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00360.2021 · Cited by 50
S‐Nitrosylation in Parkinson's Disease and Related Neurodegenerative Disorders
Chung, K. K. K., Dawson, V. L., & Dawson, T. M. (2005) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(05)96014-x · Cited by 47
α-Synuclein Aggregation: A Link Between Mitochondrial Defects and Parkinson's Disease?
Lee, S. (2003) · Antioxidants and Redox Signaling · doi:10.1089/152308603322110904 · Cited by 48
“Parkin is an E3 ubiquitin ligase (48, 49, 114, 136), an enzyme that catalyzes the conjugation of ubiquitin to proteins that are to be degraded by the 26S proteasome complex (133).”
Schurr, E., Alcaïs, A., de Léséleuc, L., & Abel, L. (2006) · Seminars in Immunology · doi:10.1016/j.smim.2006.07.005 · Cited by 48
Modification by Ubiquitin-Like Proteins: Significance in Apoptosis and Autophagy Pathways
Cajee, U.-F., Hull, R., & Ntwasa, M. M. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms130911804 · Cited by 49
“It has been demonstrated that Parkin functions as an E3 ligase and that it interacts with a number of proteins including E2 enzymes and putative substrates [123,124].”
Background
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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