# Transcript‐Level Modulation of O‐GlcNAc Transferase for Aging‐Related Neurodegenerative Diseases

## TL;DR

This paper proposes new ways to increase OGT levels in the brain to treat aging-related neurodegenerative diseases like Alzheimer's and Parkinson's.

## Contribution

The paper introduces transcript-level modulation of OGT as a novel therapeutic strategy for neurodegenerative diseases.

## Key findings

- Reduced OGT activity in the aging brain is linked to protein aggregation and neurodegeneration.
- Antisense oligonucleotides or splicing factor degraders can enhance OGT expression independently of O-GlcNAc feedback.
- Combining OGT upregulation with OGA inhibition may improve O-GlcNAc homeostasis and therapeutic outcomes.

## Abstract

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.

O‐GlcNAc Transferase (OGT) and O‐GlcNAcase (OGA) maintain O‐GlcNAc homeostasis, but OGT expression and activity decline in the aging brain, promoting protein aggregation and neurodegeneration. Current approaches raise O‐GlcNAc levels via OGA inhibition. New insights into OGT splicing enable direct OGT upregulation using ASO‐ or PROTAC‐based strategies, alone or with OGA inhibition, potentially improving control of O‐GlcNAc homeostasis and therapeutic outcomes.© 2026 WILEY‐VCH GmbH