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J. Biol. Chem., Vol. 280, Issue 9, 7800-7807, March 4, 2005

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The E46K Mutation in -Synuclein Increases Amyloid Fibril Formation^*

Eric A. Greenbaum, Charles L. Graves, Amanda J. Mishizen-Eberz, Michael A. Lupoli, David R. Lynch, S. Walter Englander¶, Paul H. Axelsen, and Benoit I. Giasson||

From the Departments of Pharmacology, ^¶Biochemistry and Biophysics, and Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

The identification of a novel mutation (E46K) in one of the KTKEGV-type repeats in the amino-terminal region of -synuclein suggests that this region and, more specifically, Glu residues in the repeats may be important in regulating the ability of -synuclein to polymerize into amyloid fibrils. It was demonstrated that the E46K mutation increased the propensity of -synuclein to fibrillize, but this effect was less than that of the A53T mutation. The substitution of Glu⁴⁶ for an Ala also increased the assembly of -synuclein, but the polymers formed can have different ultrastructures, further indicating that this amino acid position has a significant effect on the assembly process. The effect of residue Glu⁸³ in the sixth repeat of -synuclein, which lies closest to the amino acid stretch critical for filament assembly, was also studied. Mutation of Glu⁸³ to a Lys or Ala increased polymerization but perturbed some of the properties of mature amyloid. These results demonstrated that some of the Glu residues within the repeats can have significant effects on modulating the assembly of -synuclein to form amyloid fibrils. The greater effect of the A53T mutation, even when compared with what may be predicted to be a more dramatic mutation such as E46K, underscores the importance of protein microenvironment in affecting protein structure. Moreover, the relative effects of the A53T and E46K mutations are consistent with the age of onset of disease. These findings support the notion that aberrant -synuclein polymerization resulting in the formation of pathological inclusions can lead to disease.

Received for publication, October 13, 2004 , and in revised form, December 15, 2004.

^* This work was funded by a grant from the American Parkinson's Disease Association (to B. I. G. and A. J. M.-E.), NIA Grant AG20238 from the National Institutes of Health and a grant from the Alzheimer's Association (to P. H. A.), and NINDS Grant NS45986 from the National Institutes of Health (to D. R. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, 89A John Morgan Building, Philadelphia, PA 19104. Tel.: 215-573-6012; E-mail: giassonb{at}mail.med.upenn.edu.

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