Rescuable sleep and synaptogenesis phenotypes in a Drosophila model of O-GlcNAc transferase intellectual disability

Abstract
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Abstract

O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in OGT have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly Drosophila melanogaster carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA activity is required for normal neuronal development and function.

Data availability

Code used to generate Figure 2 - Supplement 1 A and C is deposited in GitHub (https://github.com/IggyCz/WBplotProfile). All the data used in our manuscript are provided as source data files for each figure.Information regarding novel genotypes and phenotypes is included in the manuscript, and will be deposited in FlyBase. Newly generated genotypes are available upon request.

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Ignacy Czajewski

Division of Molecular, Cell and Developmental Biology, University of Dundee, Dundee, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1661-5806
Bijayalaxmi Swain

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Competing interests
The authors declare that no competing interests exist.
Jiawei Xu

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Competing interests
The authors declare that no competing interests exist.
Laurin McDowall

Division of Molecular, Cell and Developmental Biology, University of Dundee, Dundee, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Andrew T Ferenbach

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Competing interests
The authors declare that no competing interests exist.
Daan MF van Aalten

2Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

For correspondence
daan@mbg.au.dk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1499-6908

Funding

Wellcome Trust (110061)

Daan MF van Aalten

Novo Nordisk Foundation Center for Basic Metabolic Research (NNF21OC0065969)

Daan MF van Aalten

National Centre for the Replacement Refinement and Reduction of Animals in Research (T001682)

Ignacy Czajewski

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.