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Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Abstract
Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.
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“Parkin, the product of PARK2, is known to be a RINGfinger-containing E3-Ub ligase”
From Limb-Girdle Muscular Dystrophy Type 2H Associated with Mutation in TRIM32, a Putative E3-Ubiquitin–Ligase Gene (2002) · cites this paper as Shimura et al. 2000
In the citing paper
“Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD).”
From USP8 regulates mitophagy by removing K6‐linked ubiquitin conjugates from parkin (2014) · cites this paper as Shimura et al, 2000
In the citing paper
“Failure of the ubiquitin-proteasome system is implicated in the pathogenesis of both sporadic and familial PD [22,23,24,94,95,96].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [24]
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“…ascertain whether parkin function mediates clearance of autophagic vacuoles, we used non-functional T240R parkin, which is a mutant form that loses its E3 ubiquitin ligase activity, leading to autosomal recessive juvenile PD (ARJPD) (Kitada et al., 1998; Lucking et al., 2000; Shimura et al., 2000).”
InfluentialRegulation of Parkin E3 ubiquitin ligase activity
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“The Parkin gene was cloned as a pathogenicity gene of autosomal recessive juvenile Par-kinsonism (AR-JP), and work from Suzuki’s group demonstrated that Parkin is an E3 ubiquitin ligase (181).”
Mitophagy Receptors in Tumor Biology
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“Parkin has multiple protein domains distinct from other RING fingertype ubiquitin-protein E3 ligases (Shimura et al. 2000; Zhang et al. 2000; Chung et al. 2001; Imai et al. 2001) and consist of an N-terminal ubiquitin-like (UBL) domain and two C-terminal RING finger domains with an IBR (inbetween ring finger) domain (…”
BackgroundInfluentialParkin-deficient mice are not more sensitive to 6-hydroxydopamine or methamphetamine neurotoxicity
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“Parkin-deficient mice used in this study lack exon 2, which encodes most of the ubiquitin-like domain believed to be required for interacting with the proteasome [56] and ubiquitinated substrates [57].”
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Parkin stabilizes PINK1 through direct interaction
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BackgroundSelf-citationA Mechanistic Review of Mitophagy and Its Role in Protection against Alcoholic Liver Disease
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“Parkin is an evolutionarily conserved E3 ubiquitin ligase [92] encoded by the Park2 gene [93] that has been shown to be required for mitophagy induction in in vitro models [40,94,95].”
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“Parkin is a 465 amino acid protein that possesses E3 ubiquitin ligase activity, and familial type mutations in parkin are predicted to be loss of function [6], suggesting that loss of parkin activity results in the gradual and abnormal accumulation of parkin substrates, which may cause familial PD.”
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“Parkin is a component of an E3 ubiquitin ligase involved in mitochondrial homeostasis (Shimura et al., 2000).”
BackgroundSelf-citationChen, T., Tan, J., Wan, Z., Zou, Y., Afewerky, H. K., Zhang, Z., & Zhang, T. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122507 · Cited by 67
Disease modification in Parkinson's disease
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Ekholm‐Reed, S., Goldberg, M. S., Schlossmacher, M. G., & Reed, S. I. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.00535-13 · Cited by 68
The Role of Ubiquitin-Protein Ligases in Neurodegenerative Disease
Ardley, H. C., & Robinson, P. A. (2004) · Neurodegenerative Diseases · doi:10.1159/000080048 · Cited by 67
Phospho-ubiquitin: upending the PINK–Parkin–ubiquitin cascade
Matsuda, N. (2016) · The Journal of Biochemistry · doi:10.1093/jb/mvv125 · Cited by 68
“The PARKIN gene was first identified as a causal gene for autosomal recessive hereditary Parkinsonism (22), and its E3 activity was reported later (23, 24).”
BackgroundDrosophila Models of Sporadic Parkinson’s Disease
Nagoshi, E. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113343 · Cited by 69
“The identification of several causative genes for rare monogenic forms of PD, such as SNCA (α-synuclein) [75], Leucine-rich repeat kinase 2 (LRRK2) [76], Parkin [77], PTEN-induced putative kinase 1 (PINK1) [78] and DJ-1 [79], overturned the traditional view that PD is not hereditary and unequivocally demonstrated the…”
BackgroundInfluentialPael receptor, endoplasmic reticulum stress, and Parkinson?s disease
Takahashi, R., & Imai, Y. (2003) · Journal of Neurology · doi:10.1007/s00415-003-1305-8 · Cited by 66
Iron accumulation in the substantia nigra of autosomal recessive juvenile parkinsonism (ARJP)
Takanashi, M., Mochizuki, H., Yokomizo, K., Hattori, N., Mori, H., Yamamura, Y., & Mizuno, Y. (2001) · Parkinsonism & Related Disorders · doi:10.1016/s1353-8020(00)00050-x · Cited by 66
Self-citationNovel parkin mutations detected in patients with early‐onset Parkinson's disease
Bertoli‐Avella, A. M., Giroud‐Benitez, J. L., Akyol, A., Barbosa, E. R., Schaap, O., van der Linde, H. C., Martignoni, E., Lopiano, L., Lamberti, P., Fincati, E., et al. (2004) · Movement Disorders · doi:10.1002/mds.20343 · Cited by 66
“Gender male (%) 34 (57) 60 11 (48) 23 23 (61) 37 Age at onset, yr (range) 33 11 (14–65) 60 28 9 (15–44) 23 39 10 (14–65) 37 Disease duration, yr (range) 15 9 (1–36) 59 20 9 (6–36) 22 13 8 (1–30) 37 Age at examination, yr (range) 49 10 (19–71) 59 49 10 (32–70) 22 49 10 (19–71) 37 Symptoms and signs at onset Bradykinesi…”
Parkinson's disease: one biochemical pathway to fit all genes?
Krüger, R., Eberhardt, O., Rieß, O., Schulz, J. B., & Rieß, O. (2002) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(02)02333-x · Cited by 65
Mitophagy restricts BAX/BAK-independent, Parkin-mediated apoptosis
Quarato, G., Mari, L., Barrows, N. J., Yang, M., Rühl, S., Chen, J., Guy, C. S., Low, J. A., Chen, T., & Green, D. R. (2023) · Science Advances · doi:10.1126/sciadv.adg8156 · Cited by 65
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Converging environmental and genetic pathways in the pathogenesis of Parkinson's disease
Burbulla, L. F., & Krüger, R. (2011) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2011.04.005 · Cited by 65
“(i) Parkin is an ubiquitin E3 ligase and therefore is an integral part of the ubiquitin-mediated proteasomal degradation pathway [55], (ii) Parkin itself is degraded by the proteasome after ubiquitination and (iii) recently, it was shown that Parkin modulates the activity of the 26S proteasome as the site of degradati…”
BackgroundThe MALDI-TOF E2/E3 Ligase Assay as Universal Tool for Drug Discovery in the Ubiquitin Pathway
Cesare, V. D., Johnson, C., Barlow, V. L., Hastie, C. J., Knebel, A., & Trost, M. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2018.06.004 · Cited by 65
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Sustained delivery of GDNF: towards a treatment for Parkinson’s disease
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Protein Engineering in the Ubiquitin System: Tools for Discovery and Beyond
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Axonal degeneration and regeneration: a mechanistic tug‐of‐war
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“cause of neurodegenerative diseases and axonal degeneration, as observed in Parkinson’s disease patients carrying mutations in the gene parkin (ubiquitin-protein ligase) (Kitada et al. 1998; Shimura et al. 2000) and in gad mice (ubiquitin carboxy-terminal hydrolase-L1) (Saigoh et al.”
Backgroundα-Synuclein Aggregates Interfere with Parkin Solubility and Distribution
Kawahara, K., Hashimoto, M., Bar‐On, P., Ho, G. J., Crews, L. A., Mizuno, H., Rockenstein, E. M., Imam, S. Z., & Masliah, E. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710418200 · Cited by 64
Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson’s disease
Shiba‐Fukushima, K., Ishikawa, K., Inoshita, T., Izawa, N., Takanashi, M., Sato, S., Onodera, O., Akamatsu, W., Okano, H., Imai, Y., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx201 · Cited by 64
Self-citationNrf2/ARE Pathway as a Therapeutic Target for the Treatment of Parkinson Diseases
Gureev, A. P., & Popov, V. N. (2019) · Neurochemical Research · doi:10.1007/s11064-018-02711-2 · Cited by 65
New mutation (R42P) of the parkin gene in the ubiquitinlike domain associated with parkinsonism
Terreni, L., Calabrese, E., Calella, A. M., Forloni, G., & Mariani, C. (2001) · Neurology · doi:10.1212/wnl.56.4.463 · Cited by 64
Ghanevati, M., & Miller, C. A. (2005) · Journal of Molecular Neuroscience · doi:10.1385/jmn:25:1:079 · Cited by 63
“Mutations in parkin, an E3 ubiquitin ligase, responsible for autosomal-recessive Parkinson’s disease (Kitada et al., 1998; Imai et al., 2000; Shimura et al., 2000), as well as frameshift mutations in ubiquitin protein”
BackgroundIchimura, K., Mungall, A. J. J., Fiegler, H., Pearson, D. M., Dunham, I., Carter, N. P., & Collins, V. P. (2005) · Oncogene · doi:10.1038/sj.onc.1209156 · Cited by 66
“Parkin, the protein product of PARK2, which is often mutated in autosomal recessive juvenile parkinsonism, is a protein– ubiquitin E3 ligase that targets substrate proteins for proteasomal degradation (Shimura et al., 2000).”
BackgroundActivation mechanisms of the E3 ubiquitin ligase parkin
Panicker, N., Dawson, V. L., & Dawson, T. M. (2017) · Biochemical Journal · doi:10.1042/bcj20170476 · Cited by 64
Xie, W., Wan, O. W., & Chung, K. K. K. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.07.014 · Cited by 66
Evidence for a Role of the Ubiquitin-Proteasome Pathway in Pancreatic Islets
López-Ávalos, M. D., Duvivier-Kali, V. F., Xu, G., Bonner‐Weir, S., Sharma, A., & Weir, G. C. (2006) · Diabetes · doi:10.2337/db05-0450 · Cited by 63
Age related mitochondrial degenerative disorders in humans
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“The Parkin protein is known to be a ubiquitin protein ligase [41] associated with autosomal recessive juvenile parkinsonism and, like Pink1, is widely expressed in the brain.”
BackgroundBaulac, S., LaVoie, M. J., Strahle, J. M., Schlossmacher, M. G., & Xia, W. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.06.014 · Cited by 63
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“It is intriguing that rare familial forms of Parkinson's disease exist in which either a gene encoding a deubiquitination enzyme (Leroy et al. 1998a,b) or a ubiquitin-protein E3 ligase, Parkin are mutated (Kitada et al. 1998; Shimura et al. 2000; Zhang et al. 2000).”
BackgroundKumar, P., Pradhan, K., Ramani, K., Ambasta, R. K., & Querfurth, H. W. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07588.x · Cited by 61
“A well characterized ubiquitin E3 ligase Parkin, is 53 kDa cytosolic protein with known substrates that are targeted for UPS degradation (Shimura et al. 2000).”
BackgroundWhat’s Behind the Decline? The Role of White Matter in Brain Aging
Hinman, J. D., & Abraham, C. R. (2007) · Neurochemical Research · doi:10.1007/s11064-007-9341-x · Cited by 66
“zyme in the ubiquitin pathway [44, 85].”
STEP 61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease
Kurup, P. K., Xu, J., Videira, R. A., Ononenyi, C., Baltazar, G., Lombroso, P. J., & Nairn, A. C. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1417423112 · Cited by 62
“Proc Natl Acad Sci USA 104(27):11441–11446.”
BackgroundCbl-mediated Ubiquitinylation and Negative Regulation of Vav
Miura-Shimura, Y., Duan, L., Rao, N. L., Reddi, A. L., Shimura, H., Rottapel, R. K., Druker, B. J., Tsygankov, A. Y., Band, V., & Band, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305656200 · Cited by 62
Self-citationWilhelmus, M. M. M., Nijland, P. G., Drukarch, B., de Vries, H. E., & van Horssen, J. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.05.040 · Cited by 62
“multiple ubiquitin molecules, thereby targeting the substrate for proteasomal degradation [29].”
BackgroundParkinson’s Disease: A Complex Interplay of Mitochondrial DNA Alterations and Oxidative Stress
Ciccone, S., Maiani, E., Bellusci, G., Diederich, M. F., & Gonfloni, S. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14022388 · Cited by 67
“Parkin has a N-terminal ubiquitin-like domain and a C-terminal RING box region with an E3 ubiquitin ligase activity [126].”
BackgroundGenetic models of Parkinson disease
Lim, K., & Ng, C.-H. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.10.005 · Cited by 63
The Basis for Selective E1-E2 Interactions in the ISG15 Conjugation System
Durfee, L. A., Kelley, M. L., & Huibregtse, J. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804069200 · Cited by 62
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Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
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“In this study, we provide several lines of evidence indicating a critical involvement of parkin deficiency in the pathogenesis of pancreatic cancer: (1) Human pancreatic cancer specimens exhibit parkin gene downregulation and copy number loss; (2) Parkin expression level negatively correlates with clinicopathological…”
BackgroundSpecificity and disease in the ubiquitin system
Chaugule, V. K., & Walden, H. (2016) · Biochemical Society Transactions · doi:10.1042/bst20150209 · Cited by 65
Parkinson's disease: from causes to mechanisms
Corti, O., Hampe, C., Darios, F. D., Ibáñez, P., Ruberg, M., & Brice, A. (2004) · Comptes Rendus Biologies · doi:10.1016/j.crvi.2004.10.009 · Cited by 61
N-myc Regulates Parkin Expression
West, A. B., Kapatos, G., O’Farrell, C., de Chavez, F. G., Chiu, K., Farrer, M. J., & Maidment, N. T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400126200 · Cited by 61
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Parkinson's Disease Modification Through Abl Kinase Inhibition: An Opportunity
Werner, M. H., & Olanow, C. W. (2021) · Movement Disorders · doi:10.1002/mds.28858 · Cited by 60
“It also acts in concert with pink1 to monitor and preserve mitochondrial integrity.(29,30,75-77) In response to oxidative or nitrosative stress, c-Abl is activated and phosphorylates parkin at Tyr(143) (pY143-parkin), resulting in the loss of its enzymatic activity.”
BackgroundMehler, M. F. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(00)01705-7 · Cited by 61
Saini, N., Oelhafen, S., Hua, H., Georgiev, O., Schaffner, W., & Büeler, H. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.05.011 · Cited by 63
Dusonchet, J., Bensadoun, J., Schneider, B. L., & Aebischer, P. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.03.013 · Cited by 61
“AR-JP-linked mutations in the parkin gene cause a loss of parkin function, with parkin mutants ultimately deficient in their ability to degrade their substrates (Shimura et al., 2000; Zhang et al., 2000; Sriram et al., 2005).”
BackgroundProfiling of Parkin-Binding Partners Using Tandem Affinity Purification
Zanon, A., Raković, A., Blankenburg, H., Doncheva, N. T., Schwienbacher, C., Serafin, A., Alexa, A., Weichenberger, C. X., Albrecht, M., Klein, C., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078648 · Cited by 61
“The Parkin protein is an E3 ubiquitin ligase responsible for the transfer of activated ubiquitin molecules to a protein substrate [6].”
BackgroundHager, L., Li, L., Pun, H., Liu, L., Hossain, M. A., Maguire, G. F., Naples, M., Baker, C., Magomedova, L., Tam, J., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.340919 · Cited by 63
Szalárdy, L., Klivènyi, P., Zádori, D., Fülöp, F., Toldi, J., & Vécsei, L. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712800167365 · Cited by 60
“involved in the polyubiquitin tagging of potentiall y dangerous and aggregation prone protein substrates for proteosomal degradation via its ubiquitin E3 ligase activity [150].”
BackgroundAutophagy, reactive oxygen species and the fate of mammalian cells
Szumiel, I. (2010) · Free Radical Research · doi:10.3109/10715762.2010.525233 · Cited by 61
“Parkin is a PARK2 gene product with a E3 ubiquitin ligase activity [55].”
BackgroundSteele‐Richardson‐Olszewski syndrome in a patient with a single C212Y mutation in the parkin protein
Morales, B., Martínez, A., Gonzalo, I., Vidal, L., Ros, R., Gómez‐Tortosa, E., Rábano, A., Ampuero, I., Sánchez, M. P., Hoenicka, J., et al. (2002) · Movement Disorders · doi:10.1002/mds.10264 · Cited by 61
Proteostasis and Movement Disorders: Parkinson's Disease and Amyotrophic Lateral SclerosisPreprint
Bosco, D. A., LaVoie, M. J., Petsko, G. A., & Ringe, D. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007500 · Cited by 61
Molecular interaction between parkin and PINK1 in mammalian neuronal cells
Um, J. W., Stichel-Gunkel, C. C., Lübbert, H., Lee, G., & Chung, K. C. (2009) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2008.12.010 · Cited by 63
“Parkin functions as an E3 ubiquitin ligase, which ubiquitinates several target proteins and enhances degrading them via ubiquitin– proteasome system (UPS) (Shimura et al., 2000).”
InfluentialParkinson's disease‐associated protein Parkin: an unusual player in cancer
Liu, J., Zhang, C., Hu, W., & Feng, Z. (2018) · 癌症：英文版 · doi:10.1186/s40880-018-0314-z · Cited by 61
How do neurons die in neurodegenerative diseases?
Kanazawa, I. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02017-2 · Cited by 60
Marteijn, J. A. F., van Emst, L., Erpelinck-Verschueren, C. A. J., Nikoloski, G., Menke, A. L., de Witte, T., Löwenberg, B., Jansen, J. H., & van der Reijden, B. A. (2005) · Blood · doi:10.1182/blood-2005-04-1450 · Cited by 60
“No interaction was observed between Triad1[1-119] and a panel of Ubcs28 tested, including CDC34, UbcH5, UbcH6, UbcH7, UbcH8, UbcH9, UbcH10, and UbcH13 (not shown).”
BackgroundManaa, W. E., Duplan, E., Goiran, T., Lauritzen, I., Vaillant-Beuchot, L., Lacas‐Gervais, S., Morais, V. A., You, H., Qi, L., Salazar, M., et al. (2021) · Autophagy · doi:10.1080/15548627.2021.1917129 · Cited by 58
“PINK1 is a key serine-threonine kinase [45] that, in conjunction with the E3-ligase [46] and transcription factor protein PRKN [47,48], behaves as an important modulator of mitophagy [49].”
BackgroundNeuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action
Mirza, F. J., Zahid, S., & Holsinger, R. M. D. (2023) · Molecules · doi:10.3390/molecules28052306 · Cited by 67
“CA was shown to prevent cell death via induction of the parkin pathway, enhancing levels of parkin protein, the UPS, and α-synuclein degradation [22].”
BackgroundCross-talk between mitochondria and proteasome in Parkinson’s disease pathogenesis
Martins-Branco, D. A. (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00017 · Cited by 63
“Parkin protein is a 465-aminoacid (a.a.) polypeptide (∼51 kDa) that plays an important role in the UPS as ubiquitin E3 ligase (Shimura et al., 2000).”
Synaptic dysfunction in genetic models of Parkinson's disease: A role for autophagy?
Plowey, E. D., & Chu, C. T. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.011 · Cited by 62
“Parkin is an E3 ubiquitin ligase (Shimura et al., 2000; Zhang et al., 2000), one of numerous ubiquitin ligases expressed in neurons that likely impact synaptic function via the UPS (Helton and Ehlers, 2008).”
Nardin, A., Schrepfer, E., & Ziviani, E. (2016) · Current Neuropharmacology · doi:10.2174/1570159x13666151030104414 · Cited by 61
“ubiquitin ligase [2], operate within the same pathway [3-5], which controls, via specific elimination of”
Xie, L. H., Tiong, C. X., & Bian, J. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00281.2011 · Cited by 59
Karri, V., Ramos, D., Bauzá‐Martinez, J., Odena, M. A., de Oliveira, E., Coort, S. L., Evelo, C. T., Mariman, E. C. M., Schuhmacher, M., & Kumar, V. (2018) · Journal of Proteomics · doi:10.1016/j.jprot.2018.06.020 · Cited by 65
Tank, E. M. H., & True, H. L. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000382 · Cited by 58
“In addition, mutations in ubiquitin processing enzymes, such as UCHL1 and Parkin, can lead to inherited forms of neurodegenerative diseases [8,9].”
BackgroundPathological Proteins in Parkinson's Disease: Focus on the Proteasome
Snyder, H. M., & Wolozin, B. L. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:3:425 · Cited by 62
“Parkin is an E3 ubiquitin-ligase enzyme (Shimura et al., 2000).”
InfluentialElkon, H., Melamed, E., & Offen, D. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:24:3:387 · Cited by 60
Huynh, D. P., Nguyen, D., Pulst‐Korenberg, J., Brice, A., & Pulst, S.-M. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.09.009 · Cited by 58
“Twenty-four hours later, cells were treated with 10 µM lactacystin for 4-hours to inhibit degradation of ubiquitinated proteins by the UPS.”
BackgroundInfluentialMoore, D. J., Dawson, V. L., & Dawson, T. M. (2003) · NeuroMolecular Medicine · doi:10.1385/nmm:4:1-2:95 · Cited by 59
“The discovery that parkin functions as an E2-dependent E3 ubiquitin protein ligase has provided tremendous insight into the role of the UPS in AR-JP(Imai et al., 2000; Shimura et al., 2000; Zhang et al., 2000a; Fig.”
BackgroundHow do Parkin mutations result in neurodegeneration?
Imai, Y., & Takahashi, R. (2004) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2004.04.002 · Cited by 57
Flach, K., Ramminger, E., Hilbrich, I., Arsalan-Werner, A., Albrecht, F., Herrmann, L., Goedert, M., Arendt, T., & Holzer, M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.029 · Cited by 58
Lee, S., Zhang, C., & Liu, X. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.606798 · Cited by 58
“As a testament to their significance in cellular health, mutations in PINK1 (8, 9) and Parkin (10, 11) have been implicated in autosomal recessive Parkinsonism.”
BackgroundRideout, H. J., Dietrich, P., Wang, Q., Dauer, W. T., & Stefanis, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405146200 · Cited by 58
Wilhelmus, M. M. M., van der Pol, S. M. A., Jansen, Q., Witte, M. E., van der Valk, P., Rozemüller, A. J. M., Drukarch, B., de Vries, H. E., & van Horssen, J. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.11.033 · Cited by 60
“Interestingly, knockout of parkin, an E3 ubiquitin ligase linked to recessive juvenile parkinsonism [3–10], and PINK1 results in mitochondrial abnormalities.”
Parkin in Parkinson’s Disease and Cancer: a Double-Edged Sword
Wahabi, K., Perwez, A., & Rizvi, M. M. A. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0879-1 · Cited by 58
“Lysosome and Proteasome Parkin is a multidomain protein which belongs to a class of enzymes termed E3 ubiquitin-protein ligases that function in the ubiquitinproteasome system (UPS) [2].”
BackgroundInfluentialDeregulation of autophagy and vesicle trafficking in Parkinson’s disease
Sheehan, P., & Yue, Z. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.013 · Cited by 56
“Mutations in Parkin, an E3 ubiquitin ligase, result in juvenile-onset PD [83].”
BackgroundReduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations
Kano, M., Takanashi, M., Oyama, G., Yoritaka, A., Hatano, T., Shiba‐Fukushima, K., Nagai, M., Nishiyama, K., Hasegawa, K., Inoshita, T., et al. (2020) · npj Parkinson s Disease · doi:10.1038/s41531-020-00137-8 · Cited by 66
Self-citationNeddylation positively regulates the ubiquitin E3 ligase activity of parkin
Um, J. W., Han, K. A., Im, E., Oh, Y., Lee, K., & Chung, K. C. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.22828 · Cited by 56
“Given that parkin interacts with the E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8 (Imai et al., 2000; Shimura et al., 2000), we tested whether NEDD8 could recruit UbcH7 or UbcH8 to parkin.”
BackgroundInfluential
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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