Nov 7, 2019

Structures of fibrils formed by α-synuclein hereditary disease mutant H50Q reveal new polymorphs

Nature Structural & Molecular Biology
David R. BoyerDavid S. Eisenberg

Abstract

Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions. Seeing the changes to the structures of amyloid fibrils bearing these mutations may help to understand these diseases. To this end, we determined the cryo-EM structures of α-synuclein fibrils containing the H50Q hereditary mutation. We find that the H50Q mutation results in two previously unobserved polymorphs of α-synuclein: narrow and wide fibrils, formed from either one or two protofilaments, respectively. These structures recapitulate conserved features of the wild-type fold but reveal new structural elements, including a previously unobserved hydrogen-bond network and surprising new protofilament arrangements. The structures of the H50Q polymorphs help to rationalize the faster aggregation kinetics, higher seeding capacity in biosensor cells and greater cytotoxicity that we observe for H50Q compared to wild-type α-synuclein.

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Mentioned in this Paper

Gene Polymorphism
Germ-Line Mutation
Hydrogen
Cytotoxicity
Structure
Mutant
Lewy Bodies
Single Nucleotide Polymorphism
Dementia
Protein Structure

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