alpha-synuclein and dimyristoylphosphatidylserine

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.

Topics: alpha-Synuclein; Amino Acid Sequence; Animals; Bacterial Proteins; Caenorhabditis elegans; Cloning, Molecular; Disease Models, Animal; Escherichia coli; Gene Expression; Genes, Reporter; Genetic Vectors; Humans; Hydrogen-Ion Concentration; Luminescent Proteins; Neurons; Parkinson Disease; Phosphatidylserines; Protein Aggregates; Protein Multimerization; Proteolipids; Recombinant Proteins; Sequence Alignment

α-Synuclein is an intrinsically disordered protein that is associated with the pathogenesis of Parkinson's disease through the processes involved in the formation of amyloid fibrils. α and β-synuclein are homologous proteins found at comparable levels in presynaptic terminals but β-synuclein has a greatly reduced propensity to aggregate and indeed has been found to inhibit α-synuclein aggregation. In this paper, we describe how sequence differences between α- and β-synuclein affect individual microscopic processes in amyloid formation. In particular, we show that β-synuclein strongly suppresses both lipid-induced aggregation and secondary nucleation of α-synuclein by competing for binding sites at the surfaces of lipid vesicles and fibrils, respectively. These results suggest that β-synuclein can act as a natural inhibitor of α-synuclein aggregation by reducing both the initiation of its self-assembly and the proliferation of its aggregates.

Topics: alpha-Synuclein; Amino Acid Sequence; beta-Synuclein; Binding, Competitive; Hydrogen-Ion Concentration; Lipids; Phosphatidylserines; Protein Aggregates; Protein Aggregation, Pathological; Protein Binding; Sequence Alignment; Surface Properties