Disrupted O-GlcNAc homeostasis links microglial dysfunction to cerebellar hypoplasia

Abstract

Pathogenic variants in O-GlcNAc transferase, which catalyses nucleocytoplasmic protein O-GlcNAcylation, cause a neurodevelopmental disorder (OGT-NDD) characterised by intellectual disability and motor impairments. However, mechanisms linking O-GlcNAc dyshomeostasis to brain development remain unclear. Longitudinal neuroimaging of an individual carrying the p.Asn648Tyr OGT-NDD variant, combined with developmental and molecular analyses of an OgtN648Y/y mouse model, revealed that the mouse phenocopied the impaired cerebellar growth in the patient. Altered OGT distribution and reduced Calbindin expression preceded reduced Purkinje and granule cell densities and molecular layer thinning, alongside increased microglial density, persistent phagocytic cup-like structures and reduced interleukin (IL)-4 levels. Pharmacological OGT inhibition reduced IL-4-induced reporter activity in vitro, while primary OgtN648Y/y microglia exhibited blunted IL-4-induced O-GlcNAcylation with enrichment of inflammatory and innate immunity programmes. These findings link impaired OGT catalytic function to postnatal cerebellar maturation during a critical developmental window and identify IL-4-associated microglial responses as a contributor to cerebellar pathology in OGT-NDD.

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BibTeX RIS

BibTeX

@misc{almeida2026disrupted,
  title = {{Disrupted O-GlcNAc homeostasis links microglial dysfunction to cerebellar hypoplasia}},
  author = {S. Almeida and S. T. Balasubramaniam and A. Jusiel and T.-S. Burmeister and L. Martins and G. U. Toft and C. Lebre and K. Ounap and P. Ilves and L. Lin and M. Romero-Ramos and J. Peca and J. Guedes and D. van Aalten},
  howpublished = {medRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.26.26363519},
  url = {https://www.medrxiv.org/content/10.64898/2026.09.26.26363519v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Disrupted O-GlcNAc homeostasis links microglial dysfunction to cerebellar hypoplasia
AU  - S. Almeida
AU  - S. T. Balasubramaniam
AU  - A. Jusiel
AU  - T.-S. Burmeister
AU  - L. Martins
AU  - G. U. Toft
AU  - C. Lebre
AU  - K. Ounap
AU  - P. Ilves
AU  - L. Lin
AU  - M. Romero-Ramos
AU  - J. Peca
AU  - J. Guedes
AU  - D. van Aalten
PY  - 2026
DA  - 2026/09/26
PB  - medRxiv
DO  - 10.64898/2026.09.26.26363519
UR  - https://www.medrxiv.org/content/10.64898/2026.09.26.26363519v1
AB  - Pathogenic variants in O-GlcNAc transferase, which catalyses nucleocytoplasmic protein O-GlcNAcylation, cause a neurodevelopmental disorder (OGT-NDD) characterised by intellectual disability and motor impairments. However, mechanisms linking O-GlcNAc dyshomeostasis to brain development remain unclear. Longitudinal neuroimaging of an individual carrying the p.Asn648Tyr OGT-NDD variant, combined with developmental and molecular analyses of an OgtN648Y/y mouse model, revealed that the mouse phenocopied the impaired cerebellar growth in the patient. Altered OGT distribution and reduced Calbindin expression preceded reduced Purkinje and granule cell densities and molecular layer thinning, alongside increased microglial density, persistent phagocytic cup-like structures and reduced interleukin (IL)-4 levels. Pharmacological OGT inhibition reduced IL-4-induced reporter activity in vitro, while primary OgtN648Y/y microglia exhibited blunted IL-4-induced O-GlcNAcylation with enrichment of inflammatory and innate immunity programmes. These findings link impaired OGT catalytic function to postnatal cerebellar maturation during a critical developmental window and identify IL-4-associated microglial responses as a contributor to cerebellar pathology in OGT-NDD.
ER  -

Abstract

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