Aggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy Body Dementia, and Multiple Systems Atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s 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 <i>in vitro. </i>Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryoEM structure of α-synuclein fibrils containing the hereditary E46K mutation to a resolution of 2.5 Å. The 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 is altered to avoid electrostatic repulsion between K46 and K80, a residue pair which would otherwise form the E46-K80 salt-bridge present in wild-type rod structures. We hypothesize that the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge acts as a kinetic trap, diverting α-synuclein into a shallower, more accessible local energy minimum. The E46K mutation therefore serves to unleash a more stable and pathogenic fibril structure.

α-Synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril polymorph

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.