The fold of [alpha]-synuclein fibrils

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