Abstract
Aggregation of human α-synuclein (αSyn) is linked to Parkinson's disease (PD) pathology. The central region of the αSyn sequence contains the non-amyloid β-component (NAC) crucial for aggregation. However, how NAC flanking regions modulate αSyn aggregation remains unclear. Using bioinformatics, mutation and NMR, we identify a 7-residue sequence, named P1 (residues 36-42), that controls αSyn aggregation. Deletion or substitution of this 'master controller' prevents aggregation at pH 7.5 in vitro. At lower pH, P1 synergises with a sequence containing the preNAC region (P2, residues 45-57) to prevent aggregation. Deleting P1 (ΔP1) or both P1 and P2 (ΔΔ) also prevents age-dependent αSyn aggregation and toxicity in C. elegans models and prevents αSyn-mediated vesicle fusion by altering the conformational properties of the protein when lipid bound. The results highlight the importance of a master-controller sequence motif that controls both αSyn aggregation and function-a region that could be targeted to prevent aggregation in disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Caenorhabditis elegans
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Cloning, Molecular
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Disease Models, Animal
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Escherichia coli / genetics
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Escherichia coli / metabolism
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Gene Expression
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Genes, Reporter
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Genetic Vectors / chemistry
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Genetic Vectors / metabolism
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Humans
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Hydrogen-Ion Concentration
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Neurons / chemistry*
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Neurons / pathology
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Parkinson Disease / genetics
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Parkinson Disease / metabolism*
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Parkinson Disease / pathology
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Phosphatidylserines / chemistry
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Protein Aggregates*
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Protein Multimerization
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Proteolipids / chemistry
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Proteolipids / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Alignment
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alpha-Synuclein / chemistry*
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alpha-Synuclein / genetics
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alpha-Synuclein / metabolism
Substances
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Bacterial Proteins
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Luminescent Proteins
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Phosphatidylserines
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Protein Aggregates
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Proteolipids
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Recombinant Proteins
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SNCA protein, human
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alpha-Synuclein
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proteoliposomes
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yellow fluorescent protein, Bacteria
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dimyristoylphosphatidylserine