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O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations

View ORCID ProfileDuc T. Huynh, Jimin Hu, Jordan R. Schneider, View ORCID ProfileKalina N. Tsolova, Erik J. Soderblom, Abigail J. Watson, View ORCID ProfileJen-Tsan Chi, View ORCID ProfileChantell S. Evans, View ORCID ProfileMichael Boyce
doi: https://doi.org/10.1101/2023.02.22.529563
Duc T. Huynh
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
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Jimin Hu
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
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Jordan R. Schneider
2Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
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Kalina N. Tsolova
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
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Erik J. Soderblom
3Proteomics and Metabolomics Shared Resource, Duke University School of Medicine, Durham, NC 27710, USA
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Abigail J. Watson
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
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Jen-Tsan Chi
2Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
4Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710, USA
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Chantell S. Evans
2Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
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Michael Boyce
1Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA
2Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, USA
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  • For correspondence: michael.boyce@duke.edu
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Abstract

The neurofilament (NF) cytoskeleton is critical for neuronal morphology and function. In particular, the neurofilament-light (NF-L) subunit is required for NF assembly in vivo and is mutated in subtypes of Charcot-Marie-Tooth (CMT) disease. NFs are highly dynamic, and the regulation of NF assembly state is incompletely understood. Here, we demonstrate that human NF-L is modified in a nutrient-sensitive manner by O-linked-β-N-acetylglucosamine (O-GlcNAc), a ubiquitous form of intracellular glycosylation. We identify five NF-L O-GlcNAc sites and show that they regulate NF assembly state. Interestingly, NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc is a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons, underlining its functional significance. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, indicating a potential link between dysregulated O-GlcNAcylation and pathological NF aggregation. Our results demonstrate that site-specific glycosylation regulates NF-L assembly and function, and aberrant NF O-GlcNAcylation may contribute to CMT and other neurodegenerative disorders.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 22, 2023.
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O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
Duc T. Huynh, Jimin Hu, Jordan R. Schneider, Kalina N. Tsolova, Erik J. Soderblom, Abigail J. Watson, Jen-Tsan Chi, Chantell S. Evans, Michael Boyce
bioRxiv 2023.02.22.529563; doi: https://doi.org/10.1101/2023.02.22.529563
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O-GlcNAcylation regulates neurofilament-light assembly and function and is perturbed by Charcot-Marie-Tooth disease mutations
Duc T. Huynh, Jimin Hu, Jordan R. Schneider, Kalina N. Tsolova, Erik J. Soderblom, Abigail J. Watson, Jen-Tsan Chi, Chantell S. Evans, Michael Boyce
bioRxiv 2023.02.22.529563; doi: https://doi.org/10.1101/2023.02.22.529563

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