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

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.