Cryo-EM structure of alpha-synuclein fibrils

TY - JOUR

T1 - Cryo-EM structure of alpha-synuclein fibrils

AU - Guerrero-Ferreira, Ricardo

AU - Taylor, Nicholas M I

AU - Mona, Daniel

AU - Ringler, Philippe

AU - Lauer, Matthias E

AU - Riek, Roland

AU - Britschgi, Markus

AU - Stahlberg, Henning

N1 - Nicholas M.I.Taylor : Present address: Structural Biology of Molecular Machines Group, Protein Structure and Function Programme, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

PY - 2018/7/3

Y1 - 2018/7/3

N2 - Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils residues 1-121, determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered b-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

AB - Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils residues 1-121, determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered b-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

U2 - 10.7554/elife.36402

DO - 10.7554/elife.36402

M3 - Journal article

C2 - 29969391

SN - 2050-084X

VL - 7

JO - eLife

JF - eLife

ER -