O-GlcNAc modification (O-GlcNAcylation) is the dynamic addition of the monosaccharide N-acetyl-glucosamine to cytosolic, nuclear and mitochondrial proteins. It is absolutely required for development and survival in mammals and insects, and it is misregulated in many human diseases, including neurodegeneration, cancer and diabetes. There are several proteins associated with neurodegenerative diseases that can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) <i>in vivo</i>, including α-synuclein, the major aggregating protein in Parkinson’s disease (PD). α-Synuclein is a 140 amino-acid protein that is prevalent in pre-synaptic neurons of the central nervous system. Unfortunately, the biochemical and biophysical effects of O-GlcNAc modification on α-Synuclein remains poorly understood. We have used synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein bearing a site-specific O-GlcNAc modification at threonine 72, threonine 75, threonine 81, serine 87, as well as triple O-GlcNAc modified proteins. We found that the presence of one or three O-GlcNAc modifications on the protein do not perturb protein’s membrane binding properties. Most of single O-GlcNAc modified proteins have ability to inhibit the nucleation step  and completely inhibit extension step of aggregation process. Additionally, several of the O-GlcNAc sites inhibit the toxicity of extracellular α-synuclein fibers that are likely playing a role in the spread of Parkinson’s disease. Thus, our data suggests that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation.

O-GlcNAc modification alters α-synuclein aggregation and neuronal toxicity

2019 Fall National Meeting

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