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

Dhavale, D. D.; Barclay, A. M.; Borcik, C. G.; Basore, K.; Gordon, I. R.; Liu, J.; Milchberg, M. H.; O'Shea, J. Y.; Rau, M. J.; Smith, Z.; Sen, S.; Summers, B.; Smith, J. W.; Warmuth, O. A.; Chen, Q.; Fitzpatrick, J. A. J.; Schwieters, C. D.; Tajkhorshid, E.; Rienstra, C. M.; Kotzbauer, P. T.

doi:10.1101/2023.01.09.523303

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bioRxiv · 10.1101/2023.01.09.523303

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

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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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Dhavale, D. D., Barclay, A. M., Borcik, C. G., Basore, K., Gordon, I. R., Liu, J., Milchberg, M. H., O'Shea, J. Y., Rau, M. J., Smith, Z., Sen, S., Summers, B., Smith, J. W., Warmuth, O. A., Chen, Q., Fitzpatrick, J. A. J., Schwieters, C. D., Tajkhorshid, E., Rienstra, C. M., Kotzbauer, P. T.. 2023-01-10. Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue. https://doi.org/10.1101/2023.01.09.523303

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