Structural Intermediates
during α-Synuclein
Fibrillogenesis on Phospholipid Vesicles
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Abstract
α-Synuclein (AS) fibrils are the main protein component
of
Lewy bodies, the pathological hallmark of Parkinson’s disease
and other related disorders. AS forms helices that bind phospholipid
membranes with high affinity, but no atomic level data for AS aggregation
in the presence of lipids is yet available. Here, we present direct
evidence of a conversion from α-helical conformation to β-sheet
fibrils in the presence of anionic phospholipid vesicles and direct
conversion to β-sheet fibrils in their absence. We have trapped
intermediate states throughout the fibril formation pathways to examine
the structural changes using solid-state NMR spectroscopy and electron
microscopy. The comparison between mature AS fibrils formed in aqueous
buffer and those derived in the presence of anionic phospholipids
demonstrates no major changes in the overall fibril fold. However,
a site-specific comparison of these fibrillar states demonstrates
major perturbations in the <i>N</i>-terminal domain with
a partial disruption of the long β-strand located in the 40s
and small perturbations in residues located in the “non-β
amyloid component” (NAC) domain. Combining all these results,
we propose a model for AS fibrillogenesis in the presence of phospholipid
vesicles