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International audience; A pathological hallmark of Huntington's disease (HD) is the formation of neuronal protein deposits containing mutant huntingtin fragments with expanded polyglutamine (polyQ) domains. Prior studies have shown the strengths of solid-state NMR (ssNMR) to probe the atomic structure of such aggregates, but have required in vitro isotopic labeling. Herein, we present an approach for the structural fingerprinting of fibrils through ssNMR at natural isotopic abundance (NA). These methods will enable the spectroscopic fingerprinting of unlabeled (e.g., ex vivo) protein aggregates and the extraction of valuable new long-range 13 C− 13 C distance constraints

Understanding fibrillogenesis at a molecular level requires detailed structural characterization of amyloid fibrils. The combination of deep UV resonance Raman (DUVRR) spectroscopy and post mortem hydrogen-deuterium exchange (HX) was utilized for probing parallel vs antiparallel beta-sheets in fibrils prepared from full-length Abeta(1-40) and Abeta(34-42) peptides, respectively. Using previously published structural data based on solid-state NMR analysis, we verified the applicability of Asher's approach for the quantitative characterization of peptide conformation in the Abeta(1-40) fibril core. We found that the conformation of the parallel beta-sheet in the Abeta(1-40) fibril core is atypical for globular proteins, while in contrast, the antiparallel beta-sheet in Abeta(32-42) fibrils is a common structure in globular proteins. In contrast to the case for globular proteins, the conformations of parallel and antiparallel beta-sheets in Abeta fibril cores are substantially different, and their differences can be distinguished by DUVRR spectroscopy.