Engineering of Non-Aggregating Alpha Synuclein Variants

Aggregation of a 140 amino acid protein, alpha synuclein (alphaS), is implicated in the pathology of Parkinson’s disease (PD). Monomeric alphaS is mostly irregularly structured, and aggregation of alphaS monomers to oligomers and fibrils is associated with conformational changes from disordered to beta-sheet rich structures. Aggregation propensity of alphaS and its naturally existing mutants has been found to be determined by combination of physicochemical properties of amino acids, such as hydrophobicity, secondary structure propensity and charges.

In this presentation, we will report that 1) one can create nearly non-aggregating alphaS variants using simple mutations without changing sequence physicochemical properties, such as secondary structure propensity, hydrophobicity and charge state, and 2) the resulting alphaS variants can inhibit alphaS aggregation by specific binding to alphaS aggregates. Our results suggest the importance of the sequence context in alphaS aggregation. Moreover, we anticipate that similar mutations may directly benefit development of aggregation modulators or aggregation state-specific binders for other amyloidogenic proteins.