Cited by 1,080Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly

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Giasson, Benoit I., Murray, Ian V.J., Trojanowski, John Q., Lee, Virginia M.-Y.·2001·Journal of Biological Chemistry

DOI 10.1074/jbc.m008919200

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Abstract

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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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.
ORCID: Giasson, Benoit I.
Murray, Ian V.J.
Trojanowski, John Q.
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)
DOI: 10.1074/jbc.m008919200
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: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 7224 d)
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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A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of α-Synuclein Is Essential for Filament Assembly

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