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Intracellular proteinaceous aggregates (Lewy bodies and Lewy neurites) of α-synuclein are hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies, and multiple systemic atrophy. However, the molecular mechanisms underlying α-synuclein aggregation into such filamentous inclusions remain unknown. An intriguing aspect of this problem is that α-synuclein is a natively unfolded protein, with little or no ordered structure under physiological conditions. This raises the question of how an essentially disordered protein is transformed into highly organized fibrils. In the search for an answer to this question, we have investigated the effects of pH and temperature on the structural properties and fibrillation kinetics of human recombinant α-synuclein. Either a decrease in pH or an increase in temperature transformed α-synuclein into a partially folded conformation. The presence of this intermediate is strongly correlated with the enhanced formation of α-synuclein fibrils. We propose a model for the fibrillation of α-synuclein in which the first step is the conformational transformation of the natively unfolded protein into the aggregation-competent partially folded intermediate.

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Protein Structure and Folding, v. 276, issue 14, p. 10737-10744