Projects per year
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 language | English |
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Article number | e1010159 |
Number of pages | 28 |
Journal | PLoS Genetics |
Volume | 18 |
Issue number | 5 |
DOIs | |
Publication status | Published - 2 May 2022 |
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Dive into the research topics of 'Intellectual disability-associated disruption of O-GlcNAc cycling impairs habituation learning in Drosophila'. Together they form a unique fingerprint.Projects
- 2 Finished
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Modelling O-GlcNAc Transferase Intellectual Disability in Drosophila (PhD Studentship)
van Aalten, D. (Investigator)
1/01/23 → 30/06/23
Project: Research
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Molecular Mechanisms of O-GICNAC Signalling (Investigator award)
van Aalten, D. (Investigator)
1/03/16 → 28/02/22
Project: Research