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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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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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