Cryo-EM structure of alpha-synuclein fibrils

被引：447

作者：

Guerrero-Ferreira, Ricardo ^{[1
]}

Taylor, Nicholas M. I. ^{[1
,5
]}

Mona, Daniel ^{[2
]}

Ringler, Philippe ^{[1
]}

Lauer, Matthias E. ^{[3
]}

Riek, Roland ^{[4
]}

Britschgi, Markus ^{[2
]}

Stahlberg, Henning ^{[1
]}

机构：

[1] Univ Basel, Biozentrum, Ctr Cellular Imaging & NanoAnalyt, Basel, Switzerland

[2] Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Neurosci Ophthalmol & Rare Dis Discovery & Transl, Neurosci Discovery, Basel, Switzerland

[3] Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Chem Biol, Basel, Switzerland

[4] Swiss Fed Inst Technol, Phys Chem Lab, Zurich, Switzerland

[5] Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Prot Res, Struct Biol Mol Machines Grp,Prot Struct & Funct, Copenhagen, Denmark

来源：

ELIFE | 2018年 / 7卷

基金：

瑞士国家科学基金会;

关键词：

MULTIPLE SYSTEM ATROPHY; FAMILIAL PARKINSONS-DISEASE; N-TERMINAL ACETYLATION; LEWY BODY DISEASE; IN-VIVO; CRYOELECTRON MICROSCOPY; CYTOPLASMIC INCLUSIONS; AMYLOID FIBRILS; NMR STRUCTURE; AGGREGATION;

D O I：

10.7554/eLife.36402

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 angstrom. Two protofilaments form a polar fibril composed of staggered beta-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.

引用

页数：18

共 84 条

[51] Phosphorylation at S87 Is Enhanced in Synucleinopathies, Inhibits α-Synuclein Oligomerization, and Influences Synuclein-Membrane Interactions [J].

Paleologou, Katerina E. ;

Oueslati, Abid ;

Shakked, Gideon ;

Rospigliosi, Carla C. ;

Kim, Hai-Young ;

Lamberto, Gonzalo R. ;

Fernandez, Claudio O. ;

Schmid, Adrian ;

Chegini, Fariba ;

Gai, Wei Ping ;

Chiappe, Diego ;

Moniatte, Marc ;

Schneider, Bernard L. ;

Aebischer, Patrick ;

Eliezer, David ;

Zweckstetter, Markus ;

Masliah, Eliezer ;

Lashuel, Hilal A. .

JOURNAL OF NEUROSCIENCE, 2010, 30 (09) :3184-3198

[52] A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology [J].

Pasanen, Petra ;

Myllykangas, Liisa ;

Siitonen, Maija ;

Raunio, Anna ;

Kaakkola, Seppo ;

Lyytinen, Jukka ;

Tienari, Pentti J. ;

Poyhonen, Minna ;

Paetau, Anders .

NEUROBIOLOGY OF AGING, 2014, 35 (09) :2180.e1-2180.e5

[53] α-Synuclein strains cause distinct synucleinopathies after local and systemic administration [J].

Peelaerts, W. ;

Bousset, L. ;

Van der Perren, A. ;

Moskalyuk, A. ;

Pulizzi, R. ;

Giugliano, M. ;

Van den Haute, C. ;

Melki, R. ;

Baekelandt, V. .

NATURE, 2015, 522 (7556) :340-+

[54] Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo [J].

Periquet, Magali ;

Fulga, Tudor ;

Myllykangas, Liisa ;

Schlossmacher, Michael G. ;

Feany, Mel B. .

JOURNAL OF NEUROSCIENCE, 2007, 27 (12) :3338-3346

[55] Mutation in the alpha-synuclein gene identified in families with Parkinson's disease [J].

Polymeropoulos, MH ;

Lavedan, C ;

Leroy, E ;

Ide, SE ;

Dehejia, A ;

Dutra, A ;

Pike, B ;

Root, H ;

Rubenstein, J ;

Boyer, R ;

Stenroos, ES ;

Chandrasekharappa, S ;

Athanassiadou, A ;

Papapetropoulos, T ;

Johnson, WG ;

Lazzarini, AM ;

Duvoisin, RC ;

DiIorio, G ;

Golbe, LI ;

Nussbaum, RL .

SCIENCE, 1997, 276 (5321) :2045-2047

[56] Critical Role of Truncated a-Synuclein and Aggregates in Parkinson's Disease and Incidental Lewy Body Disease [J].

Prasad, Kavita ;

Beach, Thomas G. ;

Hedreen, John ;

Richfield, Eric K. .

BRAIN PATHOLOGY, 2012, 22 (06) :811-825

[57] A Combinatorial NMR and EPR Approach for Evaluating the Structural Ensemble of Partially Folded Proteins [J].

Rao, Jampani Nageswara ;

Jao, Christine C. ;

Hegde, Balachandra G. ;

Langen, Ralf ;

Ulmer, Tobias S. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2010, 132 (25) :8657-8668

[58] Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides [J].

Reynolds, Nicholas P. ;

Adamcik, Jozef ;

Berryman, Joshua T. ;

Handschin, Stephan ;

Zanjani, Ali Asghar Hakami ;

Li, Wen ;

Liu, Kun ;

Zhang, Afang ;

Mezzenga, Raffaele .

NATURE COMMUNICATIONS, 2017, 8

[59] The Three-Dimensional Structures of Amyloids [J].

Riek, Roland .

COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY, 2017, 9 (02)

[60] Structure of the toxic core of α-synuclein from invisible crystals [J].

Rodriguez, Jose A. ;

Ivanova, Magdalena I. ;

Sawaya, Michael R. ;

Cascio, Duilio ;

Reyes, Francis E. ;

Shi, Dan ;

Sangwan, Smriti ;

Guenther, Elizabeth L. ;

Johnson, Lisa M. ;

Zhang, Meng ;

Jiang, Lin ;

Arbing, Mark A. ;

Nannenga, Brent L. ;

Hattne, Johan ;

Whitelegge, Julian ;

Brewster, Aaron S. ;

Messerschmidt, Marc ;

Boutet, Bastien ;

Sauter, Nicholas K. ;

Gonen, Tamir ;

Eisenberg, David S. .

NATURE, 2015, 525 (7570) :486-+

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