Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive accumulation in selected neurons of protein inclusions containing alpha-synuclein and ubiquitin. Rare inherited forms of PD are caused by autosomal dominant mutations in alpha-synuclein or by autosomal recessive mutations in parkin, an E3 ubiquitin ligase. We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates alpha-synuclein normally and that this process is altered in autosomal recessive PD. We have now identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UbcH7 as its associated E2 ubiquitin conjugating enzyme, and a new 22-kilodalton glycosylated form of alpha-synuclein (alphaSp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive PD failed to bind alphaSp22. In an in vitro ubiquitination assay, alphaSp22 was modified by normal but not mutant parkin into polyubiquitinated, high molecular weight species. Accordingly, alphaSp22 accumulated in a non-ubiquitinated form in parkin-deficient PD brains. We conclude that alphaSp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathological alphaSp22 accumulation. These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated alpha-synuclein in conventional PD.
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PARK2, the gene mutated in rare forms of Parkinson disease, is thought to work via a similar pathogenic mechanism.
“the gene mutated in rare forms of Parkinson disease, PARK2, is thought to work via a similar pathogenic mechanism.”
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. 2001
Neuronal death in Parkinson disease is thought to be a direct result of the accumulation of proteins that are no longer ubiquitinated by mutant forms of parkin and therefore are not degraded by the proteasome.
“The neuronal death seen in Parkinson disease is thought to be a direct result of the accumulation of proteins that are no longer ubiquitinated by mutant forms of parkin and that, therefore, are not degraded by the proteasome”
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. 2001
Cites
Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels.
Shevchenko, A., Wilm, M., Vorm, O., & Mann, M. F. (1996) · Analytical Chemistry · doi:10.1021/ac950914h · Cited by 9,047 · see citing works
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 · see citing works
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 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
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 · see citing works
Self-citationIvan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
AlaSOPro 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 · see citing works
The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53
Scheffner, M., Huibregtse, J. M., Vierstra, R. D., & Howley, P. M. (1993) · Cell · doi:10.1016/0092-8674(93)90384-3 · Cited by 2,387 · see citing works
Impairment of the Ubiquitin-Proteasome System by Protein Aggregation
Bence, N., Sampat, R. M., & Kopito, R. R. (2001) · Science · doi:10.1126/science.292.5521.1552 · Cited by 2,192 · see citing works
Lang, A. E., & Lozano, A. M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199810083391506 · Cited by 2,041 · see citing works
Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase
Shimura, H., Hattori, N., Kubo, S.-I., Mizuno, Y., Asakawa, S., Minoshima, S., Shimizu, N., Iwai, K., Chiba, T., Tanaka, K., et al. (2000) · Nature Genetics · doi:10.1038/77060 · Cited by 2,024 · see citing works
Self-citationThe 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 1,572 · see citing works
Association between Early-Onset Parkinson's Disease and Mutations in theParkinGene
Lücking, C. B., Dürr, A., Bonifati, V., Vaughan, J. R., Michele, G. D., Gasser, T., Harhangi, B. S., Meco, G., Denèfle, P., Wood, N. W., et al. (2000) · New England Journal of Medicine · doi:10.1056/nejm200005253422103 · Cited by 1,433 · see citing works
Joazeiro, C. A. P., & Weissman, A. M. (2000) · Cell · doi:10.1016/s0092-8674(00)00077-5 · Cited by 1,249 · see citing works
Zhang, Y., Gao, J., Chung, K. K. K., Huang, H., Dawson, V. L., & Dawson, T. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.240347797 · Cited by 982 · see citing works
Glycosylation of Nucleocytoplasmic Proteins: Signal Transduction and O-GlcNAc
Wells, L., Vosseller, K., & Hart, G. W. (2001) · Science · doi:10.1126/science.1058714 · Cited by 956 · see citing works
Imai, Y., Soda, M., & Takahashi, R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.c000447200 · Cited by 766 · see citing works
Kahle, P. J., Neumann, M., Ozmen, L., Müller, V., Jacobsen, H., Schindzielorz, A., Okochi, M., Leimer, U., van der Putten, H., Probst, A., et al. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-17-06365.2000 · Cited by 641 · see citing works
Cummings, C., Reinstein, E., Sun, Y., Antalffy, B. A., Jiang, Y.-H., Ciechanover, A., Orr, H., Beaudet, A., & Zoghbi, H. (1999) · Neuron · doi:10.1016/s0896-6273(00)81035-1 · Cited by 513 · see citing works
Is there a cause-and-effect relationship between α-synuclein fibrillization and Parkinson’s disease?
Goldberg, M. S., & Lansbury, P. T. (2000) · Nature Cell Biology · doi:10.1038/35017124 · Cited by 456 · see citing works
Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q
Mori, H., Kondo, T., Yokochi, M., Matsumine, H., Nakagawa-Hattori, Y., Miyake, T., Suda, K., & Mizuno, Y. (1998) · Neurology · doi:10.1212/wnl.51.3.890 · Cited by 370 · see citing works
Self-citationShimura, H., Hattori, N., Kubo, S., Yoshikawa, M., Kitada, T., Matsumine, H., Asakawa, S., Minoshima, S., Yamamura, Y., Shimizu, N., et al. (1999) · Annals of Neurology · doi:10.1002/1531-8249(199905)45:5 · Cited by 282 · see citing works
Self-citationTalis, A. L., Huibregtse, J. M., & Howley, P. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.11.6439 · Cited by 261 · see citing works
Familial juvenile Parkinsonism.
Carlier, G., & Jm, D. (1979) · PubMed · Cited by 261 · see citing works
Familial juvenile parkinsonism
Takahashi, H., Ohama, E., Suzuki, S. O., Horikawa, Y., Ishikawa, A., Morita, T., Tsuji, S., & 文昭, 生. (1994) · Neurology · doi:10.1212/wnl.44.3_part_1.437 · Cited by 256 · see citing works
Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations
van de Warrenburg, B. P. C., Lammens, M. M. Y., Lücking, C. B., Denèfle, P., Wesseling, P., Booij, J., Praamstra, P., Quinn, N. P., Brice, A., & Horstink, M. W. I. M. (2001) · Neurology · doi:10.1212/wnl.56.4.555 · Cited by 253 · see citing works
Rochet, J., Conway, K. A., & Lansbury, P. T. (2000) · Biochemistry · doi:10.1021/bi001315u · Cited by 221 · see citing works
Jiang, Y.-H., Lev-Lehman, E., Bressler, J., Tsai, T., & Beaudet, A. L. (1999) · The American Journal of Human Genetics · doi:10.1086/302473 · Cited by 199 · see citing works
Point Mutations (Thr240Arg and Ala311Stop) in theParkinGene
Hattori, N., Matsumine, H., Asakawa, S., Kitada, T., Yoshino, H., Elibol, B., Brookes, A. J., Yamamura, Y., Kobayashi, T., Wang, M., et al. (1998) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1998.9134 · Cited by 181 · see citing works
Self-citationICE, neuronal apoptosis and neurodegeneration
Friedlander, R. M., & Yuan, J. (1998) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4400433 · Cited by 104 · see citing works
The Ligation Systems for Ubiquitin and Ubiquitin-like Proteins
Tanaka, K., Suzuki, T., & Chiba, T. (1998) · Molecules and Cells · doi:10.1016/s1016-8478(23)13458-3 · Cited by 97 · see citing works
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 · see citing works
Disturbed sensorimotor processing during control of precision grip in patients with writer's cramp
Serrien, D. J., Burgunder, J., & Wiesendanger, M. (2000) · Movement Disorders · doi:10.1002/1531-8257(200009)15:5 · Cited by 52 · see citing works
Genetics of Parkinson's disease
Mizuno, Y., Hattori, N., & Mori, H. (1999) · Biomedicine & Pharmacotherapy · doi:10.1016/s0753-3322(99)80075-4 · Cited by 38 · see citing works
Self-citationMolécules d'étiquetage massique, non volatiles et libérables (JA Montforte et al, US)
(1998) · Biofutur · doi:10.1016/s0294-3506(99)80175-6 · Cited by 8 · see citing works
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Cited by
Sorted by citations
Dauer, W., & Przedborski, S. (2003) · Neuron · doi:10.1016/s0896-6273(03)00568-3 · Cited by 5,469 · see citing works
Hallmarks of neurodegenerative diseases
Wilson, D. M., Cookson, M. R., Van Den Bosch, L., Zetterberg, H., Holtzman, D. M., & Dewachter, I. (2023) · Cell · doi:10.1016/j.cell.2022.12.032 · Cited by 1,789 · see citing works
α-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429 · see citing works
Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States
Mattson, M. P., & Arumugam, T. V. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.05.011 · Cited by 1,242 · see citing works
Toxic Proteins in Neurodegenerative Disease
Taylor, J. P., Hardy, J., & Fischbeck, K. H. (2002) · Science · doi:10.1126/science.1067122 · Cited by 1,251 · see citing works
Zhang, W., Wang, T., Pei, Z., Miller, D. S., Wu, X., Block, M. L., Wilson, B., Zhang, W., Zhou, Y., Hong, J.-S., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-2751com · Cited by 1,265 · see citing works
Chaperone Suppression of α-Synuclein Toxicity in a <i>Drosophila</i> Model for Parkinson's Disease
Auluck, P. K., Chan, H. Y. E., Trojanowski, J. Q., Lee, V. M.-Y., & Bonini, N. M. (2002) · Science · doi:10.1126/science.1067389 · Cited by 1,227 · see citing works
Mitochondrial pathology and apoptotic muscle degeneration in <i>Drosophila parkin</i> mutants
Greene, J. C., Whitworth, A. J., Kuo, I., Andrews, L. A., Feany, M. B., & Pallanck, L. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0737556100 · Cited by 1,203 · see citing works
Epidemiology and etiology of Parkinson's disease: a review of the evidence
Wirdefeldt, K., Adami, H.-O., Cole, P., Trichopoulos, D., & Mandel, J. (2011) · European Journal of Epidemiology · doi:10.1007/s10654-011-9581-6 · Cited by 1,199 · see citing works
Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons
Goldberg, M. S., Fleming, S. M., Palacino, J. J., Cepeda, C., Lam, H. A., Bhatnagar, A., Meloni, E. G., Wu, N., Ackerson, L. C., Klapstein, G. J., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m308947200 · Cited by 913 · see citing works
Parkinson’s disease: genetics and pathogenesis
Shulman, J. M., De Jager, P. L., & Feany, M. B. (2011) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130242 · Cited by 801 · see citing works
Chung, K. K. K., Zhang, Y., Lim, K. L., Tanaka, Y., Huang, H., Gao, J., Ross, C. A., Dawson, V. L., & Dawson, T. M. (2001) · Nature Medicine · doi:10.1038/nm1001-1144 · Cited by 750 · see citing works
Altered proteasomal function in sporadic Parkinson’s disease
St. P. McNaught, K., Belizaire, R., Isacson, O., Jenner, P., & Olanow, C. W. (2003) · Experimental Neurology · doi:10.1006/exnr.2002.8050 · Cited by 573 · see citing works
Failure of the ubiquitin-proteasome system in Parkinson’s disease
McNaught, K. S. P., Olanow, C. W., Halliwell, B., Isacson, O., & Jenner, P. (2001) · Nature Reviews Neuroscience · doi:10.1038/35086067 · Cited by 519 · see citing works
Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions
Hasegawa, M., Fujiwara, H., Nonaka, T., Wakabayashi, K., Takahashi, H., Lee, V. M.-Y., Trojanowski, J. Q., Mann, D., & Iwatsubo, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208046200 · Cited by 428 · see citing works
Endoplasmic reticulum dysfunction in neurological disease
Roussel, B. D., Kruppa, A. J., Miranda, E., Crowther, D. C., Lomas, D. A., & Marciniak, S. J. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70238-7 · Cited by 441 · see citing works
González, H., Elgueta, D., Montoya, A., & Pacheco, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.07.012 · Cited by 352 · see citing works
Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases
Gan, L., & Johnson, J. A. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.12.011 · Cited by 288 · see citing works
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 · see citing works
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 · see citing works
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Jiang, H., Ren, Y., Zhao, J., & Feng, J. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh180 · Cited by 239 · see citing works
Are ubiquitination pathways central to Parkinson’s disease?
Giasson, B. I., & Lee, V. M.-Y. (2003) · Cell · doi:10.1016/s0092-8674(03)00509-9 · Cited by 234 · see citing works
Dettmer, U., Newman, A. J., Luth, E. S., Bartels, T., & Selkoe, D. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.403311 · Cited by 221 · see citing works
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McNaught, K. S. P., & Olanow, C. W. (2003) · Annals of Neurology · doi:10.1002/ana.10512 · Cited by 203 · see citing works
Identification of the ubiquitin–protein ligase that recognizes oxidized IRP2
Yamanaka, K., Ishikawa, H., Megumi, Y., Tokunaga, F., Kanie, M., Rouault, T. A., Morishima, I., Minato, N., Ishimori, K., & Iwai, K. (2003) · Nature Cell Biology · doi:10.1038/ncb952 · Cited by 181 · see citing works
Hyun, D.-H., Lee, M., Hattori, N., Kubo, S.-I., Mizuno, Y., Halliwell, B., & Jenner, P. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200666200 · Cited by 172 · see citing works
Self-citationCould a loss of α‐synuclein function put dopaminergic neurons at risk?
Perez, R. G., & Hastings, T. G. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02423.x · Cited by 133 · see citing works
General aspects of neurodegeneration
Jellinger, K. A. (2003) · Journal of Neural Transmission. Supplementa · doi:10.1007/978-3-7091-0643-3_7 · Cited by 126 · see citing works
Guerrero, E., Vasudevaraju, P., Hegde, M. L., Britton, G. B., & Rao, K. S. (2013) · Molecular Neurobiology · doi:10.1007/s12035-012-8328-z · Cited by 121 · see citing works
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Marx, F. P., Soehn, A. S., Berg, D., Melle, C., Schiesling, C., Lang, M., Kautzmann, S., Strauss, K. M., Franck, T., Engelender, S., et al. (2007) · The FASEB Journal · doi:10.1096/fj.06-6734com · Cited by 52 · see citing works
- Authors
- Shimura, H., Schlossmacher, M. G., Hattori, N., Frosch, M. P., Trockenbacher, A., Schneider, R., Mizuno, Y., Kosik, K. S., & Selkoe, D. J.
- Affiliations
- Center for Neurologic Diseases,
- Juntendo University (JP)
- Brigham and Women's Hospital (US)
- Universität Innsbruck (AT)
- Corresponding author
- Shimura, Hideki
- Schlossmacher, Michael G.
- Kosik, Kenneth S.
- Selkoe, Dennis J.
- ORCID
- Venue
- Science
- Published
- 2001-07-13
- Volume
- 293
- Issue
- 5528
- Pages
- 263-269
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2076344205
- Cited by
- 1,053
- References
- 36
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 28 · 2023: 23 · 2022: 25 · 2021: 21 · 2020: 17 · 2019: 12 · 2018: 18 · 2017: 26 · 2016: 13 · 2015: 27 · 2014: 25 · 2013: 26 · 2012: 38
- FWCI
- 83.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 02127, K08NS002127, NS 38375, P50NS038375)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, alpha-synuclein, Parkin, ubiquitination, E3 ubiquitin ligase, UbcH7, E2 ubiquitin-conjugating enzyme, protein aggregation, ubiquitin, human brain
- MeSH terms
- Brain, Brain Stem, Cell Line, Detergents, Freezing, Glycosylation, Humans, Ligases, Nerve Tissue Proteins, Parkinson Disease, Substrate Specificity, Ubiquitins, Lewy Bodies, Mutation, Missense, Parkinsonian Disorders, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Synucleins, alpha-Synuclein
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