A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly

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 vialibity 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.