Cited by 145Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

Gallardo, Gilbert, Schlüter, Oliver M, Südhof, Thomas C·2008·Nature Neuroscience

DOI 10.1038/nn2058

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Abstract

Pathogenic aggregates of alpha-synuclein are thought to contribute to the development of Parkinson's disease. Inclusion bodies containing alpha-synuclein are present in Parkinson's disease and other neurodegenerative diseases, including Alzheimer's disease. Moreover, alpha-synuclein mutations are found in cases of familial Parkinson's disease, and transgenic overexpression of alpha-synuclein causes neurodegeneration in mice. The molecular mechanisms involved, however, remain incompletely understood. Here we show that, in transgenic mice, alpha-synuclein induced neurodegeneration involves activation of the ubiquitin/proteasome system, a massive increase in apolipoprotein E (ApoE) levels and accumulation of insoluble mouse Abeta. ApoE was not protective, but was injurious, as deletion of ApoE delayed the neurodegeneration caused by alpha-synuclein and suppressed the accumulation of Abeta. Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE.

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Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
α-Synuclein in Lewy bodies
Spillantini, M. G., Schmidt, M. L., Lee, V. M.-Y., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997) · Nature · doi:10.1038/42166 · Cited by 8,382
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., et al. (1997) · Science · doi:10.1126/science.276.5321.2045 · Cited by 8,240
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Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., et al. (2003) · Science · doi:10.1126/science.1090278 · Cited by 4,383
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Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
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
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Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S. W., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)81369-0 · Cited by 3,073
α-synuclein locus duplication as a cause of familial Parkinson's disease
Chartier-Harlin, M.-C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17103-1 · Cited by 2,029
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Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration
Schmued, L. C., & Hopkins, K. J. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02513-0 · Cited by 1,218
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Ibáñez, P., Bonnet, A. M., Débarges, B., Lohmann, E., Tison, F., Agid, Y., Dürr, A., Brice, A., & Pollak, P. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17104-3 · Cited by 1,063
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Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells.
Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M., & Maeda, N. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4471 · Cited by 944
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Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871
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Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1197-263 · Cited by 830
Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice
Lee, M. K., Stirling, W., Xu, Y., Xu, X., Qui, D., Mandir, A. S., Dawson, T. M., Copeland, N. G., Jenkins, N. A., & Price, D. L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.132197599 · Cited by 824
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Coleman, M. (2005) · Nature reviews. Neuroscience · doi:10.1038/nrn1788 · Cited by 819
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Narhi, L. O., Wood, S. J., Steavenson, S., Jiang, Y., Wu, G. M., Anafi, D., Kaufman, S. A., Martin, F. H., Sitney, K. C., Denis, P., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.14.9843 · Cited by 720
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Rosahl, T. W., Spillane, D., Missler, M., Herz, J., Selig, D. K., Wolff, J. R., Hammer, R. E., Malenka, R. C., & Südhof, T. C. (1995) · Nature · doi:10.1038/375488a0 · Cited by 719
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Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M., & Mucke, L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211412398 · Cited by 607
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Ignatius, M. J., Gebicke‐Haerter, P. J., Skene, J. H. P., Schilling, J., Weisgraber, K. H., Mahley, R. W., & Shooter, E. M. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.4.1125 · Cited by 571
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Spillantini, M. G., & Goedert, M. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06900.x · Cited by 530
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Giasson, B. I., Uryu, K., Trojanowski, J. Q., & Lee, V. M. ‐. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.7619 · Cited by 510
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Dewachter, I., Dorpe, J. V., Smeijers, L., Gilis, M., Kuipéri, C., Laenen, I., Caluwaerts, N., Moechars, D., Checler, F., Vanderstichele, H., et al. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-17-06452.2000 · Cited by 108
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Chen, L., Thiruchelvam, M. J., Madura, K., & Richfield, E. K. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.02.004 · Cited by 88
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Kuo, Y., Crawford, F., MULLAN, M. J., Kokjohn, T. A., Emmerling, M. R., Weller, R. O., & Roher, A. E. (2000) · Molecular Medicine · doi:10.1007/bf03401785 · Cited by 68
Familial Dementia With Lewy Bodies
Tsuang, D. W., Dalan, A. M., Eugenio, C. J., Poorkaj, P., Limprasert, P., Spada, A. R. L., Steinbart, E. J., Bird, T. D., & Leverenz, J. B. (2002) · Archives of Neurology · doi:10.1001/archneur.59.10.1622 · Cited by 67
Influence of Apolipoprotein E Genotype on Neuronal Damage and ApoE Immunoreactivity in Human Hippocampus Following Global Ischemia
Horsburgh, K. J., Graham, D. I., Stewart, J., & Nicoll, J. A. R. (1999) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199903000-00002 · Cited by 64
Pathological 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
Observations on the progress of Wallerian degeneration in transected peripheral nerves of C57BL/Wld mice in the presence of recruited macrophages
Hall, S. M. (1993) · Journal of Neurocytology · doi:10.1007/bf01181567 · Cited by 37
Mechanisms and models of α-synuclein-related neurodegeneration
Springer, W., & Kahle, P. J. (2006) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-996-0025-8 · Cited by 16

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“Perhaps -synuclein could be one such factor, in light of the suggested synergism between the aggregation of these proteins (Masliah et al., 2001; Gallardo et al., 2008; Pletnikova et al., 2008; Clinton et al., 2010).”

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Authors: Gallardo, G., Schlüter, O. M., & Südhof, T. C.
Affiliations: The University of Texas Southwestern Medical Center (US)
European Neuroscience Institute Göttingen (DE)
Howard Hughes Medical Institute (US)
Corresponding author: Gallardo, Gilbert
ORCID: Gallardo, Gilbert
Schlüter, Oliver M
Südhof, Thomas C
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2008-02-24
Volume: 11
Issue: 3
Pages: 301-308
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn2058
OpenAlex: W1564677510
Cited by: 145
References: 48
Citations by year: 2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 8 · 2021: 6 · 2020: 5 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 9 · 2012: 13
FWCI: 8.50
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health
National Institute of Mental Health (R01MH069585)
Topics: Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: alpha-synuclein, apolipoprotein E, amyloid-beta, Parkinson's disease, Alzheimer's disease, neurodegeneration, ubiquitin-proteasome system, transgenic mice, protein aggregation, extracellular signaling
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Brain, Humans, Mice, Transgenic, Nerve Degeneration, Parkinson Disease, Peptides, Signal Transduction, Amyloid beta-Peptides, Cell Death, Mice, Knockout, Neurodegenerative Diseases, Lewy Body Disease, Ubiquitin, Proteasome Endopeptidase Complex, Mice, alpha-Synuclein

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A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides

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