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

Michaela Fenckova (Lead / Corresponding author), Villo Muha, Daniel Mariappa, Marica Catinozzi, Iggy Czajewski, Laura E. R. Blok, Andrew Ferenbach, Erik Storkebaum, Annette Schenck, Daan van Aalten (Lead / Corresponding author)

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    Abstract

    O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of 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. These findings suggest that blocking O-GlcNAc hydrolysis is a potential treatment strategy for OGT-CDG.

    Original languageEnglish
    Article numbere1010159
    Number of pages28
    JournalPLoS Genetics
    Volume18
    Issue number5
    DOIs
    Publication statusPublished - 2 May 2022

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