Rare brain disorder reveals how sugar shapes brain ageing
A rare childhood brain disorder has uncovered an unexpected mechanism: the way proteins are chemically decorated with sugar molecules has major consequences for how the brain forms. And that same mechanism may play a role in normal brain ageing.
Nearly all proteins in the body are chemically modified after they are made. One such modification is called O-GlcNAcylation, in which a specific sugar molecule is attached to proteins. This process is controlled by an enzyme called OGT. Variants in the OGT gene have recently been linked to a rare form of intellectual disability known as OGT-ID.
Researchers studied mice carrying a specific OGT variant also found in people with OGT-ID. The animals showed hyperactivity, impulsivity, and difficulties with associative learning. Imaging revealed a smaller skull, a thinner brain surface (cortex), and an underdeveloped corpus callosum (the fibre bundle connecting the two brain hemispheres). Detailed tissue analysis uncovered structural abnormalities in the outer layers of the cerebral cortex.
Which processes are disrupted?
Through protein analyses, the researchers identified which molecular pathways go wrong when O-GlcNAcylation is impaired. Multiple processes involved in brain development were found to be dysregulated. The article was published in the journal eLife.
The finding is relevant to a broader question: O-GlcNAcylation also changes during normal ageing. As cells grow older, OGT activity declines in certain brain regions. Whether disrupted protein sugar modification contributes to age-related cognitive decline has not yet been demonstrated, but the mouse model provides a platform for investigating this.
What this does not yet prove
This is an animal model of a rare genetic condition. The results apply to mice carrying a specific pathogenic variant, not to the general population. Whether the findings can be directly translated to the prevention or treatment of age-related brain problems requires further work in human tissue and clinical populations.
Even so, the study makes clear that protein sugar modification, a process that received little attention for decades, plays a fundamental role in how the brain develops and possibly how it ages.
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