O-GlcNAcylation of truncated NAC segment alters peptide-dependent effects on α-synuclein aggregation

Philip Ryan, Ming ming Xu, Andrew K. Davey, Michael Kassiou, George D. Mellick*, Santosh Rudrawar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Numerous post-translational modifications (PTMs) of the Parkinson's disease (PD) associated α-synuclein (α-syn) protein have been recognised to play critical roles in disease aetiology. Indeed, dysregulated phosphorylation and proteolysis are thought to modulate α-syn aggregation and disease progression. Among the PTMs, enzymatic glycosylation with N-acetylglucosamine (GlcNAc) onto the protein's hydroxylated amino acid residues is reported to deliver protective effects against its pathogenic processing. This modification has been reported to alter its pathogenic self-assembly. As such, manipulation of the protein's O-GlcNAcylation status has been proposed to offer a PD therapeutic route. However, targeting upstream cellular processes can lead to mechanism-based toxicity as the enzymes governing O-GlcNAc cycling modify thousands of acceptor substrates. Small glycopeptides that couple the protective effects of O-GlcNAc with the selectivity of recognition sequences may prove useful tools to modulate protein aggregation. Here we discuss efforts to probe the effects of various O-GlcNAc modified peptides on wild-type α-synuclein aggregation.

Original languageEnglish
Article number103389
JournalBioorganic Chemistry
Publication statusPublished - Jan 2020
Externally publishedYes


  • Neurodegenerative diseases
  • O-GlcNAcylation
  • Parkinson's disease
  • α-Synuclein aggregation


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