In:
PLOS Genetics, Public Library of Science (PLoS), Vol. 18, No. 5 ( 2022-5-2), p. e1010159-
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.
Type of Medium:
Online Resource
ISSN:
1553-7404
DOI:
10.1371/journal.pgen.1010159
DOI:
10.1371/journal.pgen.1010159.g001
DOI:
10.1371/journal.pgen.1010159.g002
DOI:
10.1371/journal.pgen.1010159.g003
DOI:
10.1371/journal.pgen.1010159.g004
DOI:
10.1371/journal.pgen.1010159.g005
DOI:
10.1371/journal.pgen.1010159.s001
DOI:
10.1371/journal.pgen.1010159.s002
DOI:
10.1371/journal.pgen.1010159.s003
DOI:
10.1371/journal.pgen.1010159.s004
DOI:
10.1371/journal.pgen.1010159.s005
DOI:
10.1371/journal.pgen.1010159.s006
DOI:
10.1371/journal.pgen.1010159.s007
DOI:
10.1371/journal.pgen.1010159.s008
DOI:
10.1371/journal.pgen.1010159.s009
DOI:
10.1371/journal.pgen.1010159.s010
DOI:
10.1371/journal.pgen.1010159.s011
DOI:
10.1371/journal.pgen.1010159.r001
DOI:
10.1371/journal.pgen.1010159.r002
DOI:
10.1371/journal.pgen.1010159.r003
DOI:
10.1371/journal.pgen.1010159.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2186725-2
Bookmarklink