Selective Inhibition of Aggregation and Toxicity of a Tau-Derived Peptide using Its Glycosylated Analogues

Protein glycosylation is a ubiquitous post-translational modification that regulates the folding and function of many proteins. Misfolding of protein monomers and their toxic aggregation are the hallmark of many prevalent diseases. Thus, understanding the role of glycans in protein aggregation is highly important and could contribute both to unraveling the pathology of protein misfolding diseases as well as providing a means for modifying their course for therapeutic purposes. Using β-O-linked glycosylated variants of the highly studied Tau-derived hexapeptide motif VQIVYK, which served as a simplified amyloid model, we demonstrate that amyloid formation and toxicity can be strongly attenuated by a glycan unit, depending on the nature of the glycan itself. Importantly, we show for the first time that not only do glycans hinder self-aggregation, but the glycosylated peptides are capable of inhibiting aggregation of the non-modified corresponding amyloid scaffold. Amyloid attenuation: Using β-O-linked glycosylated variants of the Tau-derived hexapeptide motif VQIVYK, which served as a simplified amyloid model scaffold, it is demonstrated that amyloid formation and toxicity can be strongly attenuated by a glycan unit, depending on the nature of the glycan itself. Moreover, the glycosylated peptides inhibit aggregation of the non-modified corresponding amyloid scaffold.