Solid-state NMR structural investigations of alpha-synuclein fibrils derived from Lewy Body dementia brain tissue
Amyloid fibrils composed of the neural protein α-synuclein (α-syn) are the primary proteinaceous constituent of insoluble deposits in the brain that are the defining pathological feature of neurodegenerative diseases, including Lewy Body dementia (LBD), Parkinson’s disease (PD), and multiple system atrophy (MSA). Despite this fact, there is currently no way to detect or quantify these fibrils in living patients, which could significantly improve diagnosis and treatment strategies. Knowledge of the atomic structures of the fibrils unique to each disease could provide the information necessary to develop specific diagnostic imaging agents, which could also be used to track disease progression. To date, several atomic models of in vitro α-syn fibrils have been developed using data from solid-state NMR (SSNMR) or cryo-EM. Here, I present an atomic model of an α-syn fibril that was derived from a deceased patient that had LBD, based on data from SSNMR and transmission electron microscopy. This structure was solved using an automated algorithm for generating long-range distance restraints, which is validated by recalculating the SSNMR in vitro structure using just a few days of computer time, compared to many months of manual analysis. The model of the LBD derived fibril shows many differences from the structures of in vitro fibrils. The defining features are a two-fold protofilament symmetry held together by interfilament contacts involving residue S87 on one filament and residues A89, A90, and A91 on the other; tight intramolecular side chain interactions involving residue I88 with residues V77 and Q79; as well as additional interactions between residue L38 and A78, defining a tight, hydrophobic core. Additionally, F94 shows long-range interactions with G73; residues G41 and S42 pack tightly against G67, G68, and A69; and N65 interacts closely with V70, defining a turn. Ultimately, these results demonstrate that the structure of the α-syn fibril present in one case of LBD is different than the previously solved in vitro structures, both at the tertiary and quaternary levels. In addition, the automated analysis accelerated the path from collecting SSNMR data to detect long-range correlations to generating a structural model, using just a fraction of the data quantity used for the previous SSNMR study.
synuclein, amyloid, fibril, structure, NMR
University of Illinois - Urbana-Champaign
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University of Illinois at Urbana-Champaign