PLoS Genetics (May 2022)

Intellectual disability-associated disruption of O-GlcNAc cycling impairs habituation learning in Drosophila.

  • Michaela Fenckova,
  • Villo Muha,
  • Daniel Mariappa,
  • Marica Catinozzi,
  • Ignacy Czajewski,
  • Laura E R Blok,
  • Andrew T Ferenbach,
  • Erik Storkebaum,
  • Annette Schenck,
  • Daan M F van Aalten

DOI
https://doi.org/10.1371/journal.pgen.1010159
Journal volume & issue
Vol. 18, no. 5
p. e1010159

Abstract

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O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of the O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognition-relevant habituation via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction, and suggests that blocking O-GlcNAc hydrolysis is a potential strategy to treat OGT-CDG.