Understanding the Role O-GlcNAc in Protein Stability

Dustin King
Simon Fraser University
Q: What did we learn?

Decreased levels of protein O-GlcNAcylation is associated with Alzheimer’s disease. However, the basic biochemical mechanisms underlying this association remain unknown. Here we show that O-GlcNAc regulates the stability of certain proteins within cells, a phenomenon which may have an impact on cellular protein levels in Alzheimer’s disease.

Q: Why is this knowledge important?

This fundamental research is important for understanding the impact O-GlcNAc has on protein structure and stability, thereby providing insights into how its dysregulation may impact Alzheimer’s disease pathology.

Q: What are the next steps?

We plan to continue exploring the influence O-GlcNAc has on protein structure and function. In doing so, we hope to improve our understanding of the fundamental mechanisms underlying neurodegeneration, findings that may ultimately contribute to the development of new therapeutic strategies.

PUBLICATIONS

Links to articles, papers and presentations connected this work:
https://pubs.acs.org/doi/10.1021/jacs.1c10621
https://pubs.acs.org/doi/10.1021/jacs.0c04710
https://www.sciencedirect.com/science/article/pii/S1367593119300663

ABSTRACT

The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer’s disease, and cancer.

However, the basic biochemical roles of O-GlcNAcylation remain largely unanswered. Several recent studies have demonstrated a clear link between O-GlcNAc and cellular thermotolerance.

It is likely that a basic function of the O-GlcNAc modification prevents the unfolding or aggregation of target proteins. Dr. King is investigating its role in protein stability. The results of this research will provide important insights into the basic molecular mechanisms governing O-GlcNAc deregulation in human disease.

Imagine a world without Alzheimer disease.