Pre-fibrillar α-synuclein variants with impaired β-structure increase neurotoxicity in Parkinson's disease models

The relation of -synuclein (S) aggregation to Parkinson's disease (PD) has long been recognized, but the mechanism of toxicity, the pathogenic species and its molecular properties are yet to be identified. To obtain insight into the function different aggregated S species have in neurotoxicity in vivo, we generated S variants by a structure-based rational design. Biophysical analysis revealed that the S mutants have a reduced fibrillization propensity, but form increased amounts of soluble oligomers. To assess their biological response in vivo, we studied the effects of the biophysically defined pre-fibrillar S mutants after expression in tissue culture cells, in mammalian neurons and in PD model organisms, such as Caenorhabditis elegans and Drosophila melanogaster. The results show a striking correlation between S aggregates with impaired -structure, neuronal toxicity and behavioural defects, and they establish a tight link between the biophysical properties of multimeric S species and their in vivo function.