The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure

Abstract

Aggregation of -synuclein is a defining molecular feature of Parkinsons disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in -synuclein are linked to both Parkinsons disease and Lewy Body Dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy Body Dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on -synuclein fibril structure is fundamental to -synuclein biology. We therefore determined the cryoEM structure of -synuclein fibrils containing the hereditary E46K mutation. The 2.5 [A] structure reveals a symmetric double protofilament in which the molecules adopt a vastly re-arranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which forms the E46-K80 salt-bridge in the wild-type fibril structure. We hypothesize that under our conditions the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts -synuclein into a kinetic trap - a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure. Significance StatementParkinsons is the second most prevalent neurodegenerative condition, leading to movement disorders, and dementia in some cases. Because of the strong association of this condition with amyloid aggregates of the protein -synuclein, structural understanding of these amyloid aggregates may be the path to eventual therapies. Our study of the structure of a variant -synuclein inherited in families afflicted with a clinical picture of parkinsonism and Lewy Body Dementia supplements recent structures of the wild type structure, and shows how a single residue change can result in a greatly changed structure that may underlie the inherited form of the disease.