Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment

Chen, Po‐Han; Hu, Jimin; Wu, Jianli; Huynh, Duc T.; Smith, Timothy J.; Pan, Samuel; Bisnett, Brittany; Smith, Alexander B; Lu, Annie; Condon, Brett M; Chi, Jen‐Tsan; Boyce, Michael

doi:10.1172/jci.insight.127751

Cited by 12 publications

(11 citation statements)

References 79 publications

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“…Previous reports identified several O-GlcNAcylation sites on rodent NF-L orthologs [47][48][49][50][51][52] , but directed studies of human NF glycosites were lacking. To discover human NF-L glycosites, we epitope-tagged the NEFL genomic locus of human cells via established CRISPR/Cas9 methods 79 (Figure s1D) and affinity-purified endogenous NF-L from cultures treated with Thiamet-G, a standard tactic to improve the technically challenging detection of O-GlcNAc moieties [80][81][82][83] . Mass spectrometry (MS) analysis identified two novel glycosites (S48, S431), complementing the previously reported glycosites from rodent NF-L 47,48 (T21, S27, S34 -human numbering of cognate rodent residues) (Figure 1F).…”

Section: Site-specific O-glcnacylation Of the Human Nf-l Head And Tai...mentioning

confidence: 99%

“…O-GlcNAc is well known to act in part as a sensor of nutrients, such as glucose and glutamine, which are biosynthetic precursors of uridine diphosphate (UDP)-GlcNAc, the nucleotide-sugar cofactor used by OGT (Figure 1A) [53][54][55] . Moreover, we have previously shown that fluctuations in nutrients or growth factors affect the O-GlcNAcylation of gigaxonin, a ubiquitin E3 ligase adaptor that targets NF proteins for proteasome-mediated destruction 82 . These results provided a precedent for metabolite-dependent regulation of NF-L through O-GlcNAc signaling.…”

Section: Nutrient Dependence Of Nf-l O-glcnacylationmentioning

confidence: 99%

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

Huynh

Schneider

et al. 2023

Preprint

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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.

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Section: Site-specific O-glcnacylation Of the Human Nf-l Head And Tai...mentioning

confidence: 99%

Section: Nutrient Dependence Of Nf-l O-glcnacylationmentioning

confidence: 99%

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

Huynh

Schneider

et al. 2023

Preprint

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“…Precisely, GAN neurons can generate autophagosomes but lack the capability of maintaining the production over prolonged induction of autophagy [ 7 , 62 ]. Several studies suggest a role of gigaxonin also in cell metabolism, where nutrient-responsive gigaxonin glycosylation forms the regulatory link between metabolism and IF turnover [ 63 ].…”

Section: Gigaxonin Plays An Important Role In If Homeostasismentioning

confidence: 99%

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

Shirakaki

Roshmi

Yokota

2022

JPM

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Giant axonal neuropathy (GAN) is a pediatric, hereditary, neurodegenerative disorder that affects both the central and peripheral nervous systems. It is caused by mutations in the GAN gene, which codes for the gigaxonin protein. Gigaxonin plays a role in intermediate filament (IF) turnover hence loss of function of this protein leads to IF aggregates in various types of cells. These aggregates can lead to abnormal cellular function that manifests as a diverse set of symptoms in persons with GAN including nerve degeneration, cognitive issues, skin diseases, vision loss, and muscle weakness. GAN has no cure at this time. Currently, an adeno-associated virus (AAV) 9-mediated gene replacement therapy is being tested in a phase I clinical trial for the treatment of GAN. This review paper aims to provide an overview of giant axonal neuropathy and the current efforts at developing a treatment for this devastating disease.

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“…Abnormal changes of the global O -GlcNAcylation level abnormal change under amyotrophic lateral sclerosis, and the progression of this disease is may be attributed to the O -GlcNAcylation of the tail domain of neurofilament protein M in spinal cord tissue [ 200 , 201 ]. The O -GlcNAcylation of gigaxonin at Ser 272 and Thr 277 mediates intermediate filament proteostasis and turnover to regulate human giant axonal neuropathy [ 202 ]. UDP- N -acetylglucosamine 2-epimerase/ N -acetylmannosamine kinase (GNE) is a bifunctional enzyme critical for sialic acid biosynthesis [ 203 ].…”

Section: O -Glcnacylation Autophagy and Skeletal Muscle Path...mentioning

confidence: 99%

Protein O-GlcNAcylation in Metabolic Modulation of Skeletal Muscle: A Bright but Long Way to Go

Liu

2022

Metabolites

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O-GlcNAcylation is an atypical, dynamic and reversible O-glycosylation that is critical and abundant in metazoan. O-GlcNAcylation coordinates and receives various signaling inputs such as nutrients and stresses, thus spatiotemporally regulating the activity, stability, localization and interaction of target proteins to participate in cellular physiological functions. Our review discusses in depth the involvement of O-GlcNAcylation in the precise regulation of skeletal muscle metabolism, such as glucose homeostasis, insulin sensitivity, tricarboxylic acid cycle and mitochondrial biogenesis. The complex interaction and precise modulation of O-GlcNAcylation in these nutritional pathways of skeletal muscle also provide emerging mechanical information on how nutrients affect health, exercise and disease. Meanwhile, we explored the potential role of O-GlcNAcylation in skeletal muscle pathology and focused on its benefits in maintaining proteostasis under atrophy. In general, these understandings of O-GlcNAcylation are conducive to providing new insights into skeletal muscle (patho) physiology.

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Gigaxonin glycosylation regulates intermediate filament turnover and may impact giant axonal neuropathy etiology or treatment

Cited by 12 publications

References 79 publications

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

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

Genetic Approaches for the Treatment of Giant Axonal Neuropathy

Protein O-GlcNAcylation in Metabolic Modulation of Skeletal Muscle: A Bright but Long Way to Go

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