Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure

Liu, C.; Li, X.; Zhao, K.; Li, Y.; Liu, Z.; Long, H.; Zhao, C.; Luo, F.; Sun, Y.; Tao, Y.; Su, X.-d.; Li, D.

doi:10.1101/870758

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bioRxiv · 10.1101/870758

Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure

Liu, C.·Li, X.·Zhao, K.·Li, Y.·Liu, Z.·Long, H.·Zhao, C.·Luo, F.·Sun, Y.·Tao, Y.·Su, X.-d.·Li, D.

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Abstract

-Synuclein (-syn) amyloid fibril, as the major component of Lewy bodies and pathological entity spreading in human brain, is closely associated with Parkinsons disease (PD) and other synucleinopathies. Several single amino-acid mutations (e.g. E46K) of -syn have been identified causative to the early onset of familial PD. Here, we determined the cryo-EM structure of a full-length -syn fibril formed by N-terminal acetylated E46K mutant -syn (Ac-E46K). The fibril structure represents a new fold of -syn, which demonstrates that the E46K mutation breaks the electrostatic interactions in the wild type (WT) -syn fibril and thus triggers the rearrangement of the overall structure. Furthermore, we show that the Ac-E46K fibril is less resistant to harsh conditions and protease cleavage, and more prone to be fragmented with a higher capability of seeding fibril formation than that of the WT fibril. Our work provides a structural view to the severe pathology of the PD familial mutation E46K of -syn and highlights the importance of electrostatic interactions in defining the fibril polymorphs.

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Liu, C., Li, X., Zhao, K., Li, Y., Liu, Z., Long, H., Zhao, C., Luo, F., Sun, Y., Tao, Y., Su, X.-d., Li, D.. 2019-12-10. Parkinson's disease associated mutation E46K of α-synuclein triggers the formation of a novel fibril structure. https://doi.org/10.1101/870758

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