a-Synuclein (asyn) is highly expressed in neurons and is associated with a number of neurodegenerative disorders, including Parkinson's Disease. aSyn adopts a variety of tertiary and quaternary structures including random coil, extended a-helices, a-helical bundles, and, in the disease-associated state, �-sheet rich aggregates. aSyn is known to be modified with the monosaccharide O-linked N-acetyl Glucosamine (O-GlcNAc), although the effect of the modification on its structure and function remains unknown. We probed the effect of O-GlcNAc modification on asyn aggregation using short peptides corresponding to a part of the asyn sequence required for �-sheet formation. Peptides without the O-GlcNAc modification accelerated asyn aggregation, while an O-GlcNAc modified peptide did not accelerate aggregation. Our findings indicate O-GlcNAc modification prevents peptides from participating in the aggregation pathway and strongly suggest that full-length, O-GlcNAc modified asyn will resist aggregation.

O-GlcNAc modification prevents peptide-dependent acceleration of α-synuclein aggregation

245th National Meeting (2013)

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