The fold of -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 -synuclein ( -syn) from monomers by intermediates into amyloid fibrils is the toxic diseasecausative mechanism. Here, we studied the structure of -syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five -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 -sheet secondary structure. The data suggest that 1-strand interacts with 2, 2 with 3, 3 with 4, and 4 with 5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of 2 3.5 nm. Based on the combination of these data and published structural studies, a fold of -syn in the fibrils is proposed and discussed.