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Abstract

Fibrillar α -synuclein (AS) is the major component of Lewy bodies, the pathological hallmark of Parkinson's disease. Mouse AS (mAS) aggregates much faster than human AS (hAS), although mAS differs from hAS at only seven positions in its primary sequence. Currently, little is known about the site-speci fi c structural differences between mAS and hAS fi brils. Here, we applied state-of-the-art solid-state nuclear magnetic resonance (ssNMR) methods to structurally characterize mAS fi brils. The assignment strategy employed a set of high-resolution 2D and 3D ssNMR spectra recorded on uniformly [ 13 C, 15 N], [1- 13 C]glucose, and [2- 13 C]glucose labeled mAS fi brils. An almost complete resonance assignment (96% of backbone amide 15 Nand 93% of all 13 C nuclei) was obtained for residues from Gly41 to Val95, which form the core of mAS fi brils. Six β -strands were identi fi ed to be within the fi bril core of mAS based on a secondary chemical shift and NHHC analysis. Intermolecular 13 C: 15 N labeled restraints obtained from mixed 1:1 13 C/ 15 N- labeled mAS fi brils reveal a parallel, in-register supramolecular β -sheet arrangement. The results were compared in detail to recent structural studies on hAS fi brils and indicate the presence of a structurally conserved motif comprising residues Glu61–Lys80.