Proteins are central to virtually every biological process, and their activity is often fine-tuned by chemical modifications after synthesis. One such regulatory mechanism is O-GlcNAcylation, the attachment of a single N-acetylglucosamine sugar molecule (O-GlcNAc) to specific amino acid residues. This dynamic and reversible modification is catalyzed by two key enzymes: O-GlcNAc transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes it.
Recent studies indicate that a substantial proportion of RNA-binding proteins—key regulators of RNA processing, stability, and translation—undergo O-GlcNAcylation. Notably, the RNA-binding protein TDP-43, when O-GlcNAcylated, shows reduced aggregation propensity. Aggregation of TDP-43 into insoluble inclusions is a hallmark of several neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS) and certain dementias, and contributes to neuronal dysfunction and loss.
Pharmacological inhibition of OGA has emerged as an effective and safe strategy to increase cellular O-GlcNAcylation, with promising results in preventing pathological protein aggregation in cellular and animal models. However, the broader effects of elevated O-GlcNAcylation on the structure, function, and interaction networks of RNA-binding proteins remain poorly understood.
The OMRP project will systematically investigate how enhanced O-GlcNAcylation alters the biochemical and functional properties of RNA-binding proteins, with a particular focus on those implicated in neurodegeneration. By combining advanced proteomics, biochemical assays, and functional analyses, this research will generate fundamental insights into the role of O-GlcNAcylation in protein homeostasis.
