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A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly
Open accessAbstract
Neuronal and oligodendrocytic aggregates of fibrillar alpha-synuclein define several diseases of the nervous system. It is likely that these inclusions impair vital metabolic processes and compromise viability of affected cells. Here, we report that a 12-amino acid stretch ((71)VTGVTAVAQKTV(82)) in the middle of the hydrophobic domain of human alpha-synuclein is necessary and sufficient for its fibrillization based on the following observations: 1) human beta-synuclein is highly homologous to alpha-synuclein but lacks these 12 residues, and it does not assemble into filaments in vitro; 2) the rate of alpha-synuclein polymerization in vitro decreases after the introduction of a single charged amino acid within these 12 residues, and a deletion within this region abrogates assembly; 3) this stretch of 12 amino acids appears to form the core of alpha-synuclein filaments, because it is resistant to proteolytic digestion in alpha-synuclein filaments; and 4) synthetic peptides corresponding to this 12-amino acid stretch self-polymerize to form filaments, and these peptides promote fibrillization of full-length human alpha-synuclein in vitro. Thus, we have identified key sequence elements necessary for the assembly of human alpha-synuclein into filaments, and these elements may be exploited as targets for the design of drugs that inhibit alpha-synuclein fibrillization and might arrest disease progression.
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“Introducing hydrophilic point mutations within the NAC significantly reduces the oligomerization and fibrillation potential of αSyn”
From α-synuclein in the pathophysiology of Alzheimer’s disease (2019) · cites this paper as [116]
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Sorrentino, Z. A., Brooks, M. M. T., Hudson, V., Rutherford, N. J., Golde, T. E., Giasson, B. I., & Chakrabarty, P. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0182-z · Cited by 79
Self-citationCharacterization of antibodies that selectively detect α-synuclein in pathological inclusions
Waxman, E. A., Duda, J. E., & Giasson, B. I. (2008) · Acta Neuropathologica · doi:10.1007/s00401-008-0375-1 · Cited by 79
Self-citationIntrinsically disordered proteins in synaptic vesicle trafficking and release
Snead, D., & Eliezer, D. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev118.006493 · Cited by 79
Amyloid-Beta Peptides Trigger Aggregation of Alpha-Synuclein In Vitro
Köppen, J., Schulze, A., Machner, L., Wermann, M., Eichentopf, R., Guthardt, M., Hähnel, A., Klehm, J., Kriegeskorte, M.-C., Hartlage‐Rübsamen, M., et al. (2020) · Molecules · doi:10.3390/molecules25030580 · Cited by 79
Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts
Teil, M., Arotçarena, M.-L., Faggiani, E., Laferrière, F., Bézard, E., & Dehay, B. (2020) · Biomolecules · doi:10.3390/biom10030391 · Cited by 80
Characterization of kinases involved in the phosphorylation of aggregated α‐synuclein
Waxman, E. A., & Giasson, B. I. (2010) · Journal of Neuroscience Research · doi:10.1002/jnr.22537 · Cited by 78
Self-citationA β-synuclein mutation linked to dementia produces neurodegeneration when expressed in mouse brain
Fujita, M., Sugama, S., Sekiyama, K., Sekigawa, A., Tsukui, T., Nakai, M., Waragai, M., Takenouchi, T., Takamatsu, Y., Wei, J., et al. (2010) · Nature Communications · doi:10.1038/ncomms1101 · Cited by 78
Lemkau, L., Comellas, G., Kloepper, K. D., Woods, W. S., George, J. M., & Rienstra, C. M. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.306902 · Cited by 78
Evidence of Native α-Synuclein Conformers in the Human Brain
Gould, N. S., Mor, D. E., Lightfoot, R. T., Malkus, K. A., Giasson, B. I., & Ischiropoulos, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.c113.538249 · Cited by 80
Self-citation
Metadata
- Authors
- Giasson, B. I., Murray, I. V. J., Trojanowski, J. Q., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 276
- Issue
- 4
- Pages
- 2380-2386
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2166789153
- Cited by
- 1,080
- References
- 36
- Citations by year
- 2026: 33 · 2025: 60 · 2024: 77 · 2023: 58 · 2022: 78 · 2021: 59 · 2020: 65 · 2019: 51 · 2018: 57 · 2017: 51 · 2016: 36 · 2015: 36 · 2014: 39 · 2013: 32 · 2012: 36
- FWCI
- 21.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- 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, fibrillization, filament assembly, hydrophobic domains, beta-synuclein, protease resistance, amyloid fibrils, neurodegenerative diseases
- MeSH terms
- Amino Acid Sequence, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Nervous System Diseases, Peptide Fragments, Protein Binding, Protein Conformation, Recombinant Proteins, Synucleins, alpha-Synuclein, beta-Synuclein
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