Structural Comparison of Mouse and Human α-Synuclein Amyloid Fibrils by Solid-State NMR

LV, G; KUMAR, A; ANDRÉS BINOLFI, RODOLFO M. RASIA, CARLOS W. BERTONCINI, MARCELO CEOLÍN, CHRISTIAN GRIESINGER, THOMAS M. JOVIN , CLAUDIO O. FERNÁNDEZLLER, K; ORCELLET, ML; RIEDEL, D; FERNANDEZ, CO; BECKER, S; LANGE, A

JOURNAL OF MOLECULAR BIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2012 p. 99 - 111

0022-2836

Fibrillar α-synuclein (AS) is the major component of Lewy bodies, thepathological hallmark of Parkinson´s disease. Mouse AS (mAS) aggregatesmuch faster than human AS (hAS), although mAS differs from hAS at onlyseven positions in its primary sequence. Currently, little is known about thesite-specific structural differences between mAS and hAS fibrils. Here, weapplied state-of-the-art solid-state nuclear magnetic resonance (ssNMR)methods to structurally characterize mAS fibrils. The assignment strategyemployed a set of high-resolution 2D and 3D ssNMR spectra recorded onuniformly [13C, 15N], [1-13C]glucose, and [2-13C]glucose labeled mAS fibrils.An almost complete resonance assignment (96% of backbone amide 15N and93% of all 13C nuclei) was obtained for residues from Gly41 to Val95, whichform the core of mAS fibrils. Six β-strands were identified to be within thefibril core of mAS based on a secondary chemical shift and NHHC analysis.Intermolecular 13C:15N labeled restraints obtained from mixed 1:1 13C/15NlabeledmAS fibrils reveal a parallel, in-register supramolecular β-sheetarrangement. The results were compared in detail to recent structural studieson hAS fibrils and indicate the presence of a structurally conserved motifcomprising residues Glu61?Lys80.