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Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation

Chuanqi Sun, Kang Zhou, Peter DePaola IV, Woo Shik Shin, Trae Hillyer, Michael R. Sawaya, View ORCID ProfileZ. Hong Zhou, Lin Jiang
doi: https://doi.org/10.1101/2022.03.11.483992
Chuanqi Sun
1Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
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Kang Zhou
2California Nano Systems Institute, UCLA, Los Angeles, CA 90095, USA
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Peter DePaola IV
1Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
3Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-DOE Institute, UCLA, Los Angeles, CA 90095, USA
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Woo Shik Shin
4Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA
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Trae Hillyer
4Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH 44272, USA
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Michael R. Sawaya
3Departments of Biological Chemistry and Chemistry and Biochemistry, Howard Hughes Medical Institute, UCLA-DOE Institute, UCLA, Los Angeles, CA 90095, USA
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Z. Hong Zhou
2California Nano Systems Institute, UCLA, Los Angeles, CA 90095, USA
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Lin Jiang
1Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA
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  • For correspondence: jianglin@ucla.edu
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Abstract

Synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple systems atrophy (MSA) have the same hallmark pathologic feature of misfolded α-synuclein protein accumulation in the brain. PD patients who carry α-syn hereditary mutations tend to have an earlier onset and more severe clinical symptoms and pathology than sporadic PD patients who carry wild-type (WT) α-syn. Therefore, revealing the structural effect of α-syn hereditary mutations on the wild-type fibril structure can help us understand synucleinopathies’ structural basis. Here, we present a 3.38 Å cryo-electron microscopy structure of α-synuclein fibrils containing the hereditary A53E mutation. The A53E fibril is symmetrically composed of two protofilaments, as are many other synucleopathic structures – including WT. Interestingly, the interface between the protofilaments in A53E has significantly less buried surface area than all other documented fibril structures of α-syn and its other mutants. The A53E fibril also exhibits slower formation/growth in in vitro fibrillation experiment compared to other mutants. This implies that the structural differences - both in the protofilament and between each protofilament of A53E – change the aggregation mechanism, or in the least, its kinetics of formation. These differences influence the molecular characteristics of each fibril mutant and likely plays a macro-scale role in progressing one clinical pathology over another.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 30, 2022.
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Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation
Chuanqi Sun, Kang Zhou, Peter DePaola IV, Woo Shik Shin, Trae Hillyer, Michael R. Sawaya, Z. Hong Zhou, Lin Jiang
bioRxiv 2022.03.11.483992; doi: https://doi.org/10.1101/2022.03.11.483992
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Cryo-EM structure of amyloid fibril formed by α-synuclein hereditary A53E mutation
Chuanqi Sun, Kang Zhou, Peter DePaola IV, Woo Shik Shin, Trae Hillyer, Michael R. Sawaya, Z. Hong Zhou, Lin Jiang
bioRxiv 2022.03.11.483992; doi: https://doi.org/10.1101/2022.03.11.483992

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