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

Nat Commun. 2024 Mar 29;15(1):2750. doi: 10.1038/s41467-024-46832-5.

Authors

Dhruva D Dhavale^#¹, Alexander M Barclay^#², Collin G Borcik³, Katherine Basore⁴, Deborah A Berthold⁵, Isabelle R Gordon¹, Jialu Liu¹, Moses H Milchberg³, Jennifer Y O'Shea¹, Michael J Rau⁴, Zachary Smith¹, Soumyo Sen⁶, Brock Summers⁴, John Smith⁷, Owen A Warmuth³, Richard J Perrin^{1

8}, Joel S Perlmutter^{1

9}, Qian Chen⁷, James A J Fitzpatrick⁴, Charles D Schwieters¹⁰, Emad Tajkhorshid⁶, Chad M Rienstra^{11

12

13

14}, Paul T Kotzbauer¹⁵

Affiliations

¹ Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA.
² Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
³ Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA.
⁴ Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁵ Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
⁶ 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, Urbana, IL, 61801, USA.
⁷ Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
⁸ Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
⁹ Department of Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, 63110, USA.
¹⁰ Computational Biomolecular Magnetic Resonance Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
¹¹ Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. crienstra@wisc.edu.
¹² Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, 53706, USA. crienstra@wisc.edu.
¹³ Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI, 53706, USA. crienstra@wisc.edu.
¹⁴ National Magnetic Resonance Facility at Madison, University of Wisconsin-Madison, Madison, WI, 53706, USA. crienstra@wisc.edu.
¹⁵ Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA. kotzbauerp@wustl.edu.

^# Contributed equally.

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.

MeSH terms

Cryoelectron Microscopy
Humans
Lewy Bodies / pathology
Lewy Body Disease* / pathology
Parkinson Disease* / pathology
alpha-Synuclein / chemistry

Substances

alpha-Synuclein
SNCA protein, human

Abstract

MeSH terms

Substances

Grants and funding