Nature Communications (Mar 2024)
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
Affiliations
- Dhruva D. Dhavale
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Alexander M. Barclay
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign
- Collin G. Borcik
- Department of Biochemistry, University of Wisconsin-Madison
- Katherine Basore
- Center for Cellular Imaging, Washington University School of Medicine
- Deborah A. Berthold
- Department of Chemistry, University of Illinois at Urbana-Champaign
- Isabelle R. Gordon
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Jialu Liu
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Moses H. Milchberg
- Department of Biochemistry, University of Wisconsin-Madison
- Jennifer Y. O’Shea
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Michael J. Rau
- Center for Cellular Imaging, Washington University School of Medicine
- Zachary Smith
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Soumyo Sen
- Theoretical and Computational Biophysics Group, NIH Resource for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign
- Brock Summers
- Center for Cellular Imaging, Washington University School of Medicine
- John Smith
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign
- Owen A. Warmuth
- Department of Biochemistry, University of Wisconsin-Madison
- Richard J. Perrin
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Joel S. Perlmutter
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- Qian Chen
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign
- James A. J. Fitzpatrick
- Center for Cellular Imaging, Washington University School of Medicine
- Charles D. Schwieters
- Computational Biomolecular Magnetic Resonance Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
- Emad Tajkhorshid
- Theoretical and Computational Biophysics Group, NIH Resource for Macromolecular Modeling and Visualization, Beckman Institute for Advanced Science and Technology, Department of Biochemistry, and Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign
- Chad M. Rienstra
- Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign
- Paul T. Kotzbauer
- Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine
- DOI
- https://doi.org/10.1038/s41467-024-46832-5
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 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.
