O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding

ACS Chem Biol. 2017 Apr 21;12(4):1020-1027. doi: 10.1021/acschembio.7b00113. Epub 2017 Feb 22.


The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson's disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation. However, the effects of the other eight O-GlcNAcylation sites that have been identified were unknown. Here, we use a similar synthetic strategy to investigate the consequences of this modification at one of these sites, serine 87. We show that O-GlcNAcylation at this site also inhibits α-synuclein aggregation but to a lesser extent than that for the same modification at threonine 72. However, we also find that this modification does not affect the membrane-binding properties of α-synuclein, which differentiates it from phosphorylation at the same site. These results further support the development of therapies that can elevate O-GlcNAcylation of α-synuclein to slow the progression of Parkinson's disease.

MeSH terms

  • Acetylglucosamine / metabolism*
  • Acylation
  • Cell Membrane / metabolism
  • Escherichia coli / metabolism
  • Protein Binding
  • Serine / metabolism*
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / metabolism*


  • alpha-Synuclein
  • Serine
  • Acetylglucosamine