Bioorganic and Medicinal Chemistry
Bioorganic and Medicinal Chemistry
5 years ago

O-GlcNAc modification inhibits the calpain-mediated cleavage of α-synuclein

O-GlcNAc modification inhibits the calpain-mediated cleavage of α-synuclein
The major protein associated with Parkinson’s disease (PD) is α-synuclein, as it can form toxic amyloid-aggregates that are a hallmark of many neurodegenerative diseases. α-Synuclein is a substrate for several different posttranslational modifications (PTMs) that have the potential to affect its biological functions and/or aggregation. However, the biophysical effects of many of these modifications remain to be established. One such modification is the addition of the monosaccharide N-acetyl-glucosamine, O-GlcNAc, which has been found on several α-synuclein serine and threonine residues in vivo. We have previously used synthetic protein chemistry to generate α-synuclein bearing two of these physiologically relevant O-GlcNAcylation events at threonine 72 and serine 87 and demonstrated that both of these modifications inhibit α-synuclein aggregation. Here, we use the same synthetic protein methodology to demonstrate that these same O-GlcNAc modifications also inhibit the cleavage of α-synuclein by the protease calpain. This further supports a role for O-GlcNAcylation in the modulation of α-synuclein biology, as proteolysis has been shown to potentially affect both protein aggregation and degradation.

Publisher URL: www.sciencedirect.com/science

DOI: S0968089617305953

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