The modification of proteins in the cytosol, nucleus, and mitochondria by the monosaccharide <i>N</i>-acetyl-glucosamine (O-GlcNAc) is required for development in mammals and Drosophila and is misregulated in a variety of diseases. One of the general functions of O-GlcNAcylation is to respond to changes in metabolism and cellular stress. Interestingly, several of the proteins that are known to form toxic aggregates in neurodegenerative diseases are known to be O-GlcNAc modified, suggesting that this modification may modulate this process. Here, I will present our investigation of the effects of O-GlcNAcylation on the biochemistry of α-synuclein, the major aggregating protein in Parkinson’s disease and related dementias. Specifically, I will describe our use of synthetic protein chemistry to build O-GlcNAcylated α-synuclein and how these synthetic proteins have enabled us to characterize O-GlcNAc as an inhibitor of α-synuclein aggregation and the associated toxicity.

Understanding the site-specific consequences of O-GlcNAc using synthetic protein chemistry

254th National Meeting (2017)

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