Structural and functional landscape of α-synuclein fibril conformations amplified from cerebrospinal fluid

Sokratian, A.; Zhou, Y.; Xu, E.; Viverette, E.; Dillard, L.; Yuan, Y.; Li, J.; Matarangas, A.; Bouvette, J.; Borgnia, M. J.; Bartesaghi, A.; West, A.

doi:10.1101/2022.07.13.499896

bioRxiv · 10.1101/2022.07.13.499896

Structural and functional landscape of α-synuclein fibril conformations amplified from cerebrospinal fluid

Sokratian, A.·Zhou, Y.·Xu, E.·Viverette, E.·Dillard, L.·Yuan, Y.·Li, J.·Matarangas, A.·Bouvette, J.·Borgnia, M. J.·Bartesaghi, A.·West, A.

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Abstract

Lewy body dementias are pathologically defined by the deposition of -synuclein fibrils into inclusions throughout the brain. Cerebrospinal fluid(CSF) in disease harbors circulating -synuclein-fibril seeds, and parental -synuclein fibrils can template core structure into amplified fibrils. Using cryo-electron microscopy, we identify six novel -synuclein fibril assemblies amplified from ten CSF samples (3.8[A] to 2.9[A] nominal resolutions). Fibrils are classified based on two types of filament interaction, two types of {beta}-sheet stacking, and two types of hydrophobic pocket. CSF-amplified fibril products have one, two, or three distinct assemblies each. Six of ten samples share a common fibril assembly. Within this classification, the fibrils have distinct profiles in amyloid dye binding, and dramatically different potencies in both seeding new inclusions in neurons and evoked microglial pro-inflammatory responses. However, no single structural feature predicts functional phenotypes. Our results highlight CSF as a valuable resource to identify novel -synuclein assemblies potentially important in disease.

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Sokratian, A., Zhou, Y., Xu, E., Viverette, E., Dillard, L., Yuan, Y., Li, J., Matarangas, A., Bouvette, J., Borgnia, M. J., Bartesaghi, A., West, A.. 2022-07-13. Structural and functional landscape of α-synuclein fibril conformations amplified from cerebrospinal fluid. https://doi.org/10.1101/2022.07.13.499896

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