Molecular agents that specifically bind and neutralize misfolded and toxic amyloids may find application in attenuating progression of neuronal diseases. However, high structural similarities between the wild-type and mutant amyloid limit the utility of this approach. We are addressing this challenge by converting promiscuous proteins into highly specific aggregation inhibitors of SOD1, Aβ42 and Tau. We utilize computational algorithms for mapping protein surfaces predisposed to inhibitor intermolecular interactions to construct a focused protein inhibitor library, complemented with an experimental platform based on yeast surface display for affinity and specificity screening.
On and off Aβ aggregation pathways in solution and in membranes. In the presence of membranes (ii), endogenous Aβ forms a large portion of on-pathway molecules with an α-helical structure in the early aggregation stages, followed by the formation of mature anti-parallel β-sheet fibrils, which exhibit higher toxicity than the parallel β-sheet Aβ fibrils formed in aqueous solution (i). Binding to membrane components (e.g., GM1) allows the anti-parallel β-sheet Aβ fibrils to bind to molecules, such as toll-like receptors (TLRs), and thereby to initiate cell death by apoptosis. Similarly, in the presence of DOPC and DOPG, Aβ forms globular aggregates that are toxic to cells. Red circles indicate the toxic species in each pathway; large arrows indicate accelerated formation of the species.
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