RT Journal Article
SR Electronic
T1 The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 868869
DO 10.1101/868869
A1 David R. Boyer
A1 Binsen Li
A1 Chuanqi Sun
A1 Weijia Fan
A1 Kang Zhou
A1 Michael P. Hughes
A1 Michael R. Sawaya
A1 Lin Jiang
A1 David S. Eisenberg
YR 2019
UL http://biorxiv.org/content/early/2019/12/08/868869.abstract
AB 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 in vitro. 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. The 2.5 Å 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 α-synuclein into a kinetic trap – a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.Significance Statement Parkinson’s 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 α-synuclein, structural understanding of these amyloid aggregates may be the path to eventual therapies. Our study of the structure of a variant α-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.