The 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.
Florian Malard (Thu,) studied this question.
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