Cryo-EM structure of alpha-Synuclein Fibrils Harboring the Dementia with Lewy Bodies - Associated E83Q Mutation

Aggregation of -synuclein (-Syn) into amyloid fibrils underlies the pathology of synucleinopathies. Rare familial mutations can modulate -Syn aggregation and may give rise to distinct fibril conformations linked to disease heterogeneity. The E83Q mutation, identified in a Dementia with Lewy Body disease (DLB) patient with atypical Lewy body distribution, has been shown to accelerate -Syn aggregation and enhance neuronal seeding, yet its structural basis remains unclear. Here, we determined the cryo-electron microscopy structure at 3.4 [A] resolution of recombinant full-length human -Syn fibrils harboring the E83Q mutation. The fibrils adopt a double-protofilament architecture with a conserved Greek-key-like core spanning residues 36-99, stabilized by intra- and inter-filament salt bridges. Despite this conserved fold, the E83Q mutation induces a distinct local rearrangement within the hydrophobic region: substitution of Glu83 with Gln reorients residue 83 inward, abolishing solvent exposure and altering interactions with the N-terminal region. This structural shift brings the hydrophobic region closer to the N-terminus, shielding residues implicated in post-translational modification and ligand binding. Our findings reveal how a single charge-neutralizing mutation reshapes -Syn fibril architecture, providing a structural framework to understand the enhanced aggregation and pathogenic properties associated with the E83Q variant.