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

Duc T. Huynh, Kalina N. Tsolova, Abigail J. Watson, Sai Kwan Khal, Jordan R. Green, Di Li, Jimin Hu, Erik J. Soderblom, Jen-Tsan Chi, Chantell S. Evans and Michael Boyce ()
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Duc T. Huynh: Duke University School of Medicine
Kalina N. Tsolova: Duke University School of Medicine
Abigail J. Watson: Duke University School of Medicine
Sai Kwan Khal: Duke University School of Medicine
Jordan R. Green: Duke University School of Medicine
Di Li: Duke University School of Medicine
Jimin Hu: Duke University School of Medicine
Erik J. Soderblom: Duke University School of Medicine
Jen-Tsan Chi: Duke University School of Medicine
Chantell S. Evans: Duke University School of Medicine
Michael Boyce: Duke University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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. NF-L engages in O-GlcNAc-mediated protein-protein interactions with itself and with the NF component α-internexin, implying that O-GlcNAc may be a general regulator of NF architecture. We further show that NF-L O-GlcNAcylation is required for normal organelle trafficking in primary neurons. Finally, several CMT-causative NF-L mutants exhibit perturbed O-GlcNAc levels and resist the effects of O-GlcNAcylation on NF assembly state, suggesting 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.

Date: 2023
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DOI: 10.1038/s41467-023-42227-0

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