Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel

Binsen Li, Peng Ge, Kevin A. Murray, Phorum Sheth, Meng Zhang, Gayatri Nair, Michael R. Sawaya, Woo Shik Shin, David R. Boyer, Shulin Ye, David S. Eisenberg (), Z. Hong Zhou () and Lin Jiang ()
Additional contact information
Binsen Li: UCLA
Peng Ge: UCLA
Kevin A. Murray: UCLA
Phorum Sheth: UCLA
Meng Zhang: UCLA
Gayatri Nair: UCLA
Michael R. Sawaya: UCLA
Woo Shik Shin: UCLA
David R. Boyer: UCLA
Shulin Ye: UCLA
David S. Eisenberg: UCLA
Z. Hong Zhou: UCLA
Lin Jiang: UCLA

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: Abstract α-Synuclein (aSyn) fibrillar polymorphs have distinct in vitro and in vivo seeding activities, contributing differently to synucleinopathies. Despite numerous prior attempts, how polymorphic aSyn fibrils differ in atomic structure remains elusive. Here, we present fibril polymorphs from the full-length recombinant human aSyn and their seeding capacity and cytotoxicity in vitro. By cryo-electron microscopy helical reconstruction, we determine the structures of the two predominant species, a rod and a twister, both at 3.7 Å resolution. Our atomic models reveal that both polymorphs share a kernel structure of a bent β-arch, but differ in their inter-protofilament interfaces. Thus, different packing of the same kernel structure gives rise to distinct fibril polymorphs. Analyses of disease-related familial mutations suggest their potential contribution to the pathogenesis of synucleinopathies by altering population distribution of the fibril polymorphs. Drug design targeting amyloid fibrils in neurodegenerative diseases should consider the formation and distribution of concurrent fibril polymorphs.

Date: 2018
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DOI: 10.1038/s41467-018-05971-2

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