Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease
1998; Nature Portfolio; Volume: 4; Issue: 11 Linguagem: Inglês
10.1038/3311
ISSN1546-170X
AutoresKelly A. Conway, James D. Harper, Peter T. Lansbury,
Tópico(s)Neurological disorders and treatments
ResumoTwo mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (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 alpha-synuclein fibril formation may contribute to the early onset of familial PD.
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