Michael J. Volles

TL;DR: It is reported here that protofibrils differ markedly from fibrils with respect to their interactions with synthetic membranes, and the possibility that the toxicity of alpha-synuclein fibrillization may derive from an oligomeric intermediate, rather than the fibril, has implications regarding the design of therapeutics for PD.

TL;DR: It is concluded that the pathogenesis of Parkinson's disease may involve membrane permeabilization by protofibrillar alpha-synuclein, the extent of which will be strongly dependent on the in vivo conditions.

TL;DR: This work favors a toxic protofibril scenario, and proposes that the pathogenic species is transiently populated during the process of fibrillization, suggesting that toxicity may arise from pore-like prot ofibrils that cause membrane permeabilization.

TL;DR: To investigate the alpha-synuclein protein and its role in Parkinson's disease, a library of random point mutants both in vitro and in yeast was screened to find variants in an unbiased way that could help to understand the sequence-phenotype relationship.

TL;DR: Evidence is provided that oligomeric intermediates of the alpha-synuclein fibrillization pathway, termed protofibrils, might be neurotoxic, which suggests that cytosolic dopamine in dopaminergic neurons promotes the accumulation of toxic alpha- Synuclein protofibils, which might explain why these neurons are most vulnerable to degeneration in PD.