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

Dhruva D. Dhavale; Alexander M. Barclay; Collin G. Borcik; Katherine Basore; Deborah A. Berthold; Isabelle R. Gordon; Jialu Liu; Moses H. Milchberg; Jennifer Y. O’Shea; Michael J. Rau; Zachary Smith; Soumyo Sen; Brock Summers; John Smith; Owen A. Warmuth; Richard J. Perrin; Joel S. Perlmutter; Qian Chen; James A.J. Fitzpatrick; Charles D. Schwieters; Emad Tajkhorshid; Chad M. Rienstra; Paul T. Kotzbauer

doi:10.1038/s41467-024-46832-5

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

Dhruva D. Dhavale, Alexander M. Barclay, Collin G. Borcik, Katherine Basore, Deborah A. Berthold, Isabelle R. Gordon, Jialu Liu, Moses H. Milchberg, Jennifer Y. O’Shea, Michael J. Rau, Zachary Smith, Soumyo Sen, Brock Summers, John Smith, Owen A. Warmuth, Richard J. Perrin, Joel S. Perlmutter, Qian Chen, James A.J. Fitzpatrick, Charles D. SchwietersEmad Tajkhorshid, Chad M. Rienstra, Paul T. Kotzbauer

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	2750
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-46832-5
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Online availability

10.1038/s41467-024-46832-5

Library availability

Discover UIUC Full Text

Cite this

Dhavale, D. D., Barclay, A. M., Borcik, C. G., Basore, K., Berthold, D. A., Gordon, I. R., Liu, J., Milchberg, M. H., O’Shea, J. Y., Rau, M. J., Smith, Z., Sen, S., Summers, B., Smith, J., Warmuth, O. A., Perrin, R. J., Perlmutter, J. S., Chen, Q., Fitzpatrick, J. A. J., ... Kotzbauer, P. T. (2024). Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue. Nature communications, 15(1), Article 2750. https://doi.org/10.1038/s41467-024-46832-5

Dhavale, DD, Barclay, AM, Borcik, CG, Basore, K, Berthold, DA, Gordon, IR, Liu, J, Milchberg, MH, O’Shea, JY, Rau, MJ, Smith, Z, Sen, S, Summers, B, Smith, J, Warmuth, OA, Perrin, RJ, Perlmutter, JS, Chen, Q, Fitzpatrick, JAJ, Schwieters, CD, Tajkhorshid, E, Rienstra, CM & Kotzbauer, PT 2024, 'Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue', Nature communications, vol. 15, no. 1, 2750. https://doi.org/10.1038/s41467-024-46832-5

@article{b5fc0af386544d95a9d1b4d6fc4be878,

title = "Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue",

abstract = "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.",

author = "Dhavale, {Dhruva D.} and Barclay, {Alexander M.} and Borcik, {Collin G.} and Katherine Basore and Berthold, {Deborah A.} and Gordon, {Isabelle R.} and Jialu Liu and Milchberg, {Moses H.} and O{\textquoteright}Shea, {Jennifer Y.} and Rau, {Michael J.} and Zachary Smith and Soumyo Sen and Brock Summers and John Smith and Warmuth, {Owen A.} and Perrin, {Richard J.} and Perlmutter, {Joel S.} and Qian Chen and Fitzpatrick, {James A.J.} and Schwieters, {Charles D.} and Emad Tajkhorshid and Rienstra, {Chad M.} and Kotzbauer, {Paul T.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-46832-5",

language = "English (US)",

volume = "15",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

AU - Dhavale, Dhruva D.

AU - Barclay, Alexander M.

AU - Borcik, Collin G.

AU - Basore, Katherine

AU - Berthold, Deborah A.

AU - Gordon, Isabelle R.

AU - Liu, Jialu

AU - Milchberg, Moses H.

AU - O’Shea, Jennifer Y.

AU - Rau, Michael J.

AU - Smith, Zachary

AU - Sen, Soumyo

AU - Summers, Brock

AU - Smith, John

AU - Warmuth, Owen A.

AU - Perrin, Richard J.

AU - Perlmutter, Joel S.

AU - Chen, Qian

AU - Fitzpatrick, James A.J.

AU - Schwieters, Charles D.

AU - Tajkhorshid, Emad

AU - Rienstra, Chad M.

AU - Kotzbauer, Paul T.

PY - 2024/12

Y1 - 2024/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85188898810&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85188898810&partnerID=8YFLogxK

U2 - 10.1038/s41467-024-46832-5

DO - 10.1038/s41467-024-46832-5

M3 - Article

C2 - 38553463

AN - SCOPUS:85188898810

SN - 2041-1723

VL - 15

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 2750

ER -

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

Abstract

ASJC Scopus subject areas

Online availability

Library availability

Related links

Fingerprint

Cite this