Certain Metals Trigger Fibrillation of Methionine-oxidized α-synuclein

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The aggregation and fibrillation of α-synuclein has been implicated as a key step in the etiology of Parkinson's disease and several other neurodegenerative disorders. In addition, oxidative stress and certain environmental factors, including metals, are believed to play an important role in Parkinson's disease. Previously, we have shown that methionine-oxidized human α-synuclein does not fibrillate and also inhibits fibrillation of unmodified α-synuclein (Uversky, V. N., Yamin, G., Souillac, P. O., Goers, J., Glaser, C. B., and Fink, A. L. (2002) FEBS Lett. 517, 239–244). Using dynamic light scattering, we show that the inhibition results from stabilization of the monomeric form of Met-oxidized α-synuclein. We have now examined the effect of several metals on the structural properties of methionine-oxidized human α-synuclein and its propensity to fibrillate. The presence of metals induced partial folding of both oxidized and non-oxidized α-synucleins, which are intrinsically unstructured under conditions of neutral pH. Although the fibrillation of α-synuclein was completely inhibited by methionine oxidation, the presence of certain metals (Ti3+, Zn2+, Al3+, and Pb2+) overcame this inhibition. These findings indicate that a combination of oxidative stress and environmental metal pollution could play an important role in triggering the fibrillation of α-synuclein and thus possibly Parkinson's disease.

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Protein Structure and Folding, v. 278, issue 30, p. 27630-27635