Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease

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Abstract
Two mutations in the gene encoding α-synuclein have been linked to early-onset Parkinson's disease1,2,3 (PD). α-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain4. This connection between genetics and pathology suggests that the α-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied α-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of α-synuclein (A53T and A30P) are, like wild-type α-synuclein5 (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of α-synuclein fibril formation may contribute to the early onset of familial PD.