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Intellectual disability-associated disruption of O-GlcNAc cycling impairs habituation learning in Drosophila.
- Source :
- PLoS Genetics, Vol 18, Iss 5, p e1010159 (2022)
- Publication Year :
- 2022
- Publisher :
- Public Library of Science (PLoS), 2022.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 15537390 and 15537404
- Volume :
- 18
- Issue :
- 5
- Database :
- Directory of Open Access Journals
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.267272faa05a4b8e9499b0a7286ccd9b
- Document Type :
- article
- Full Text :
- https://doi.org/10.1371/journal.pgen.1010159