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

Dhruva D Dhavale; Alexander M Barclay; Collin G Borcik; Katherine Basore; Isabelle R Gordon; Jialu Liu; Moses H Milchberg; Jennifer O'shea; Michael J Rau; Zachary Smith; Soumyo Sen; Brock Summers; John Smith; Owen A Warmuth; Qian Chen; James A J Fitzpatrick; Charles D Schwieters; Emad Tajkhorshid; Chad M Rienstra; Paul T Kotzbauer

doi:10.1101/2023.01.09.523303

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

bioRxiv [Preprint]. 2023 Jan 10:2023.01.09.523303. doi: 10.1101/2023.01.09.523303.

Authors

Dhruva D Dhavale¹, Alexander M Barclay², Collin G Borcik³, Katherine Basore⁴, Isabelle R Gordon¹, Jialu Liu¹, Moses H Milchberg³, Jennifer O'shea¹, Michael J Rau⁴, Zachary Smith¹, Soumyo Sen⁵, Brock Summers⁴, John Smith⁶, Owen A Warmuth³, Qian Chen⁶, James A J Fitzpatrick⁴, Charles D Schwieters⁷, Emad Tajkhorshid⁵, Chad M Rienstra^{2

3

8

9}, Paul T Kotzbauer¹

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 Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁵ 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.
⁶ Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, IL 61801, USA.
⁷ Computational Biomolecular Magnetic Resonance Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53706 USA.
⁹ National Magnetic Resonance Facility at Madison, University of Wisconsin-Madison, Madison, WI 53706, USA.

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. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise two protofilaments with pseudo-2₁ helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The 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 landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.

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Abstract

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