Increased O-GlcNAc Transferase Expression as an Approach to Improving Function in the Aging Brain
There are so many detrimental age-related changes in gene expression that it will always be possible to pick out any one gene exhibiting altered expression and spend years on research and development aimed at fixing this one specific issue. Restoring youthful expression of any one gene in any one tissue is an achievable goal for present day medical research and development, though costs and regulatory hurdles remain challenging. Expression can be increased via gene therapy vectors, or reduced via various approaches, such as small interfering RNA, that attack some part of the process of gene expression. The most productive future will not be one of picking through thousands of changes one by one, however, but instead a matter of attempts to restore youthful gene expression more generally, for most or all genes, through some form of reprogramming. Still, the one by one approach remains the primary focus of the research community, as this example illustrates, though at least researchers now tend to favor regulatory genes that influence the expression of large numbers of other genes.
O-GlcNAc Transferase (OGT) is responsible for the addition of β-O-linked N-acetyl-D-glucosamine (O-GlcNAc) to serine and threonine residues, thereby regulating more than 8000 human proteins through O-GlcNAcylation. In the brain, reduced O-GlcNAc levels, which can arise from insufficient OGT activity, have been increasingly linked to aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis.
While current strategies focus on restoring O-GlcNAc levels via O-GlcNAcase (OGA) inhibition, recent discoveries highlight transcript-level regulation of OGT as a direct and promising therapeutic target. This concept article explores the role of intron detention and decoy exon-mediated splicing repression in limiting OGT pre-mRNA maturation and proposes the use of antisense oligonucleotides or selective splicing factor degraders to promote productive splicing and nuclear export of OGT mRNA. By enhancing OGT expression independently of O-GlcNAc feedback, these approaches aim to restore proteostasis and improve resilience to neurodegeneration, offering a novel therapeutic approach for aging-related neurodegenerative diseases.