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 () and Paul T. Kotzbauer ()
Additional contact information
Dhruva D. Dhavale: Washington University School of Medicine
Alexander M. Barclay: University of Illinois at Urbana-Champaign
Collin G. Borcik: University of Wisconsin-Madison
Katherine Basore: Washington University School of Medicine
Deborah A. Berthold: University of Illinois at Urbana-Champaign
Isabelle R. Gordon: Washington University School of Medicine
Jialu Liu: Washington University School of Medicine
Moses H. Milchberg: University of Wisconsin-Madison
Jennifer Y. O’Shea: Washington University School of Medicine
Michael J. Rau: Washington University School of Medicine
Zachary Smith: Washington University School of Medicine
Soumyo Sen: University of Illinois at Urbana-Champaign
Brock Summers: Washington University School of Medicine
John Smith: University of Illinois at Urbana-Champaign
Owen A. Warmuth: University of Wisconsin-Madison
Richard J. Perrin: Washington University School of Medicine
Joel S. Perlmutter: Washington University School of Medicine
Qian Chen: University of Illinois at Urbana-Champaign
James A. J. Fitzpatrick: Washington University School of Medicine
Charles D. Schwieters: National Institutes of Health
Emad Tajkhorshid: University of Illinois at Urbana-Champaign
Chad M. Rienstra: University of Illinois at Urbana-Champaign
Paul T. Kotzbauer: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46832-5

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