Cryo-EM structure of alpha-synuclein fibrils

Ricardo Guerrero-Ferreira; Nicholas M I Taylor; Daniel Mona; Philippe Ringler; Matthias E Lauer; Roland Riek; Markus Britschgi; Henning Stahlberg

doi:10.7554/elife.36402

Cryo-EM structure of alpha-synuclein fibrils

Ricardo Guerrero-Ferreira, Nicholas M I Taylor, Daniel Mona, Philippe Ringler, Matthias E Lauer, Roland Riek, Markus Britschgi, Henning Stahlberg

165 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	eLife
Vol/bind	7
ISSN	2050-084X
DOI	https://doi.org/10.7554/elife.36402
Status	Udgivet - 3 jul. 2018
Udgivet eksternt	Ja

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10.7554/elife.36402Licens: CC BY

http://europepmc.org/articles/pmc6092118?pdf=renderLicens: CC BY

Citationsformater

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title = "Cryo-EM structure of alpha-synuclein fibrils",

abstract = "Parkinson{\textquoteright}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 {\AA}. 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.",

author = "Ricardo Guerrero-Ferreira and Taylor, {Nicholas M I} and Daniel Mona and Philippe Ringler and Lauer, {Matthias E} and Roland Riek and Markus Britschgi and Henning Stahlberg",

note = "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 ",

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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 -

Cryo-EM structure of alpha-synuclein fibrils

Abstract

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