Open access publications in the SLU publication database

Abstract

Most proteins need to adopt a three-dimensional structure in order to function properly. Misfolding, or inability of proteins to fold, is associated with a number of diseases. In a subset of these disorders, the misfolded protein or peptide selfassembles into stable, β-sheet rich structures known as amyloid fibrils. Alzheimer's disease is associated with the aggregation of the amyloid β-peptide (Aβ) into oligomers and amyloid fibrils. Aβ has a discordant, i.e β-sheet preferring, helix prone to misfold and it has been proposed that stabilization of this helix could prevent aggregation. We have designed small molecules that bind to this region and stabilize Aβ in a helical conformation. This interaction reduced fibril formation and cell toxicity of the peptide and also restored a memory-linked electrophysiological function in mouse hippocampal slices treated with Aβ. Moreover, when administered orally, these compounds had a rescuing effect in a Drosophila melanogaster model of Aβ aggregation. Another protein capable of forming amyloid-like fibrils in association with disease, is the human lung surfactant protein C, SP-C, which has a discordant transmembrane helix. SP-C is expressed as a pro-protein with a C-terminal, CTC, which has a Brichos domain with unknown function. Here, we show that CTC is important for the stability and folding of the pro-protein in the endoplasmic reticulum (ER). It is able to prevent the mature SP-C from aggregating in vitro, and is shown to bind specifically to non-helical segments and to amino acids that have been reported to promote membrane insertion in the ER. Together these data suggest a chaperone function for CTC, targeting transmembrane regions that have not attained an α-helical conformation. CTC interacts with and reduces amyloidlike fibril formation of Aβ as well as an additional amyloidogenic peptide – medin. In conclusion this thesis explores two new strategies for preventing protein misfolding and amyloid fibril formation. The first approach utilizes designed ligands to trap the Alzheimer's disease associated Aβ in its native helical structure. The second employs a novel, natural chaperone that bridges folding of transmembrane regions and anti-amyloid properties.