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The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of [alpha]-synuclein ([alpha]-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of [alpha]-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five [beta]-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of [beta]-sheet secondary structure. The data suggest that [beta]-strand interacts with [beta]2, [beta]2 with [beta]3, [beta]3 with [beta]4, and [beta]4 with [beta]5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of [approximately equal to]2 x 3.5 nm. Based on the-combination of these data and published structural studies, a fold of [alpha]-syn in the fibrils is proposed and discussed. amyloid | NMR | Parkinson's disease | structure | aggregation

Alzheimer's disease is the most fatal neurodegenerative disorder wherein the process of amyloid-[beta] (A[beta]) amyloidogenesis appears causative. Here, we present the 3D structure of the fibrils comprising A[beta](1-42), which was obtained by using hydrogen-bonding constraints from quenched hydrogen/deuterium-exchange NMR, side-chain packing constraints from pairwise mutagenesis studies, and parallel, in-register [beta]-sheet arrangement from previous solidstate NMR studies. Although residues 1-17 are disordered, residues 18-42 form a [beta]-strand-turn-[beta]-strand motif that contains two intermolecular, parallel, in-register [beta]-sheets that are formed by residues 18-26 ([beta]1) and 31-42 ([beta]2). At least two molecules of A[beta](1-42) are required to achieve the repeating structure of a protofilament. Intermolecular side-chain contacts are formed between the odd-numbered residues of strand [beta]1 of the nth molecule and the even-numbered residues of strand [beta]2 of the (n--1)th molecule. This interaction pattern leads to partially unpaired [beta]-strands at the fibrillar ends, which explains the sequence selectivity, the cooperativity, and the apparent unidirectionality of A[beta] fibril growth. It also provides a structural basis for fibrillization inhibitors. NMR | hydrogen/deuterium exchange