Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

被引：23

作者：

Dhavale, Dhruva D. ^{[1
,2
]}

Barclay, Alexander M. ^{[3
]}

Borcik, Collin G. ^{[4
]}

Basore, Katherine ^{[5
]}

Berthold, Deborah A. ^{[6
]}

Gordon, Isabelle R. ^{[1
,2
]}

Liu, Jialu ^{[1
,2
]}

Milchberg, Moses H. ^{[4
]}

O'Shea, Jennifer Y. ^{[1
,2
]}

Rau, Michael J. ^{[5
]}

Smith, Zachary ^{[1
,2
]}

Sen, Soumyo ^{[3
,7
]}

Summers, Brock ^{[5
]}

Smith, John ^{[8
]}

Warmuth, Owen A. ^{[4
]}

Perrin, Richard J. ^{[1
,2
,9
]}

Perlmutter, Joel S. ^{[1
,2
,10
]}

Chen, Qian ^{[8
]}

Fitzpatrick, James A. J. ^{[5
]}

Schwieters, Charles D. ^{[11
]}

Tajkhorshid, Emad ^{[3
,7
]}

Rienstra, Chad M. ^{[3
,4
,12
,13
]}

Kotzbauer, Paul T. ^{[1
,2
]}

机构：

[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[2] Washington Univ, Hope Ctr Neurol Disorders, Sch Med, St. Louis, MO 63110 USA

[3] Univ Illinois, Ctr Biophys & Quantitat Biol, Urbana, IL 61801 USA

[4] Univ Wisconsin Madison, Dept Biochem, Madison, WI 53706 USA

[5] Washington Univ, Sch Med, Ctr Cellular Imaging, St Louis, MO 63110 USA

[6] Univ Illinois, Dept Chem, Urbana, IL 61801 USA

[7] Univ Illinois, Theoret & Computat Biophys Grp, NIH Resource Macromol Modeling & Visualizat, Beckman Inst Adv Sci & Technol,Dept Biochem, Urbana, IL 61801 USA

[8] Univ Illinois, Dept Mat Sci & Engn, Urbana, IL 61801 USA

[9] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA

[10] Washington Univ, Sch Med, Dept Radiol Neurosci Phys Therapy & Occupat Therap, St Louis, MO 63110 USA

[11] NIDDK, Computat Biomol Magnet Resonance Core, NIH, Bethesda, MD 20892 USA

[12] Univ Wisconsin Madison, Morgridge Inst Res, Madison, WI 53706 USA

[13] Univ Wisconsin Madison, Natl Magnet Resonance Facil Madison, Madison, WI 53706 USA

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

美国国家卫生研究院;

关键词：

SOLID-STATE NMR; MACROMOLECULAR STRUCTURE DETERMINATION; OVERHAUSER ENHANCEMENT SPECTRA; MASS-PER-LENGTH; PARKINSONS-DISEASE; RESONANCE ASSIGNMENTS; MOLECULAR-STRUCTURE; CROSS-POLARIZATION; PATHOGENIC FIBRIL; ROTATING SOLIDS;

D O I：

10.1038/s41467-024-46832-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn. The accumulation of alpha-synuclein fibrils within neurons is the defining feature of Lewy body dementia (LBD). Here the authors report a method to produce large quantities of alpha-synuclein fibrils that reproduce the complex structure of the fibrils that accumulate in LBD brain tissue.

引用

页数：18

共 101 条

[1] Alpha-synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease [J].

Appel-Cresswell, Silke ;

Vilarino-Guell, Carles ;

Encarnacion, Mary ;

Sherman, Holly ;

Yu, Irene ;

Shah, Brinda ;

Weir, David ;

Thompson, Christina ;

Szu-Tu, Chelsea ;

Trinh, Joanne ;

Aasly, Jan O. ;

Rajput, Alex ;

Rajput, Ali H. ;

Stoessl, A. Jon ;

Farrer, Matthew J. .

MOVEMENT DISORDERS, 2013, 28 (06) :811-813

[2] Binding of the Radioligand SIL23 to α-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent [J].

Bagchi, Devika P. ;

Yu, Lihai ;

Perlmutter, Joel S. ;

Xu, Jinbin ;

Mach, Robert H. ;

Tu, Zhude ;

Kotzbauer, Paul T. .

PLOS ONE, 2013, 8 (02)

[3]

Baldus M, 1998, MOL PHYS, V95, P1197, DOI 10.1080/00268979809483251

[4] 13C and 15N resonance assignments of alpha synuclein fibrils amplified from Lewy Body Dementia tissue [J].

Barclay, Alexander M. ;

Dhavale, Dhruva D. ;

Borcik, Collin G. ;

Milchberg, Moses H. ;

Kotzbauer, Paul T. ;

Rienstra, Chad M. .

BIOMOLECULAR NMR ASSIGNMENTS, 2023, 17 (2) :281-286

[5] Resonance assignments of an α-synuclein fibril prepared in Tris buffer at moderate ionic strength [J].

Barclay, Alexander M. ;

Dhavale, Dhruva D. ;

Courtney, Joseph M. ;

Kotzbauer, Paul T. ;

Rienstra, Chad M. .

BIOMOLECULAR NMR ASSIGNMENTS, 2018, 12 (01) :195-199

[6] Homonuclear radio frequency-driven recoupling in rotating solids [J].

Bennett, AE ;

Rienstra, CM ;

Griffiths, JM ;

Zhen, WG ;

Lansbury, PT ;

Griffin, RG .

JOURNAL OF CHEMICAL PHYSICS, 1998, 108 (22) :9463-9479

[7] CHEMICAL-SHIFT CORRELATION SPECTROSCOPY IN ROTATING SOLIDS - RADIO FREQUENCY-DRIVEN DIPOLAR RECOUPLING AND LONGITUDINAL EXCHANGE [J].

BENNETT, AE ;

OK, JH ;

GRIFFIN, RG ;

VEGA, S .

JOURNAL OF CHEMICAL PHYSICS, 1992, 96 (11) :8624-8627

[8] Mass Spectrometric Analysis of Lewy Body-Enriched α-Synuclein in Parkinson's Disease [J].

Bhattacharjee, Payel ;

Ohrfelt, Annika ;

Lashley, Tammaryn ;

Blennow, Kaj ;

Brinkrnalm, Ann ;

Zetterberg, Henrik .

JOURNAL OF PROTEOME RESEARCH, 2019, 18 (05) :2109-2120

[9] Structural and functional characterization of two alpha-synuclein strains [J].

Bousset, Luc ;

Pieri, Laura ;

Ruiz-Arlandis, Gemma ;

Gath, Julia ;

Jensen, Poul Henning ;

Habenstein, Birgit ;

Madiona, Karine ;

Olieric, Vincent ;

Boeckmann, Anja ;

Meier, Beat H. ;

Melki, Ronald .

NATURE COMMUNICATIONS, 2013, 4

[10] The α-synuclein hereditary mutation E46K unlocks a more stable, pathogenic fibril structure [J].

Boyer, David R. ;

Li, Binsen ;

Sun, Chuanqi ;

Fan, Weijia ;

Zhou, Kang ;

Hughes, Michael P. ;

Sawaya, Michael R. ;

Jiang, Lin ;

Eisenberg, David S. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2020, 117 (07) :3592-3602

← 1 2 3 4 5 6 7 8 9 10 →