Contact between the 1 and 2 Segments of -Synuclein that Inhibits Amyloid Formation

Conversion of the intrinsically disordered protein -synuclein (-syn) into amyloid aggregates is a key process in Parkinson's disease. The sequence region 35-59 contains -strand segments 1 and 2 of -syn amyloid fibril models and most disease-related mutations. 1 and 2 frequently engage in transient interactions in monomeric -syn. The consequences of 1-2 contacts are evaluated by disulfide engineering, biophysical techniques, and cell viability assays. The double-cysteine mutant -synCC, with a disulfide linking 1 and 2, is aggregation-incompetent and inhibits aggregation and toxicity of wild-type -syn. We show that -syn delays the aggregation of amyloid- peptide and islet amyloid polypeptide involved in Alzheimer's disease and type2 diabetes, an effect enhanced in the -synCC mutant. Tertiary interactions in the 1-2 region of -syn interfere with the nucleation of amyloid formation, suggesting promotion of such interactions as a potential therapeutic approach.