Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

Yanpallewar, Sudhirkumar; Wang, Ting; Koh, Dow Rhoon; Quarta, Eros; Fulgenzi, Gianluca; Tessarollo, Lino

doi:10.1038/srep32957

Cited by 31 publications

(25 citation statements)

References 41 publications

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“…Previous studies have demonstrated increased formalin-induced inflammatory pain in Nedd4-2 heterozygotes compared to wild-type (76,79), aligning with these findings for ciguatoxin inducedspontaneous pain as both results show reduction in NEDD4-2 activity is associated with greater pain sensitivities. The mechanism for increased nociception is hypothesised to be due to diminished NaV recycling in the absence of Nedd4-2 and a resultant increase in membrane excitability and pain transmission.…”

Section: Discussionsupporting

confidence: 84%

“…In this study, this hypothesis was not proven by measuring the expression of NaVs in the DRG for Nedd4-2 KO mice, which leaves room for additional experimentation to define the microscopic effects of NEDD4-2 on DRG channel populations through methods such as tissue straining or immunofluorescence. The effects of NEDD4-2 on DRG NaV channels is still uncertain, with one study showing that complete knockout of Nedd4-2 in nociceptive neurones caused an increase in the concentrations of both NaV1.7 and 1.8 (76), while another was unable to demonstrate changes in NaV1.7 and 1.8 levels in the DRG using incomplete knockout mice (79). This may suggest that reduced levels of Nedd4-2 in incomplete knockout models is not substantial enough to cause changes in NaV concentrations, and changes can only be seen with complete knockouts.…”

Section: Discussionmentioning

confidence: 99%

“…This gene is responsible for controlling the presence of voltage-gated ion channels along the membranes of neurons. (76,79) Ubiquitination is a biological process involved in the tagging of membrane proteins for internalisation and recycling. The process involves many steps, the last step involving ubiquitin E3 ligase which must recognise specific motifs carried by membrane proteins.…”

Section: Nedd4lmentioning

confidence: 99%

“…Nedd4-2 has been associated with the regulation of NaV expression and trafficking, with NaV1.7 and NaV1.8 being selectively downregulated in neurons where NEDD4-2 levels have been overexpressed (75,76). The mechanism for this regulation is believed to be executed via the ubiquitin associated processes controlled by NEDD4-2 E3 ubiquitin ligase expression (79). Ubiquitin is a compound used for marking specific protein and is composed of alpha helices (blue), beta sheets (green) and lysine residues (yellow).…”

Section: Introductionmentioning

confidence: 99%

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Identification of pain genes contributing to ciguatoxin-induced pain using haplotype-based computational genetic mapping in mice

Soh¹

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Pain is a complex process involving numerous underlying genetic contributions still not completely appreciated, which may explain the high degree of interindividual differences seen with nociception. Chronic pain is responsible for a significant socioeconomic burden on the individual as well as society and is affected by several patient specific aspects including physiological, psychological and PUBLICATIONS DURING CANDIDATURE No publications.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Nedd4lmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of pain genes contributing to ciguatoxin-induced pain using haplotype-based computational genetic mapping in mice

Soh¹

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“…NEDD4L is a HECT E3 ubiquitin ligase with multiple substrates regulating, among others, neuronal functions (Ekberg et al, 2014;Yanpallewar et al, 2016;Todaro et al, 2018). NEDD4L is highly expressed in the cortical plate, the ventricular zone, and the ganglionic eminences in the fetal brain of mice (Broix et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Recurrent NEDD4L Variant in Periventricular Nodular Heterotopia, Polymicrogyria and Syndactyly

et al. 2020

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NEDD4L encodes an ubiquitin ligase which is expressed in the cortex and ventricular zone of the fetal brain. Missense variants in NEDD4L have been reported in nine patients with periventricular nodular heterotopia (PNH), polymicrogyria, cleft palate, and syndactyly. All reported variants are located in the HECT domain, causing deregulation of signaling pathways, including the AKT/mTOR pathway. Here we describe a first familial case with four affected members with a high degree of intra-familial phenotypic variability. Phenotypic features in the proband consisted of severe neurodevelopmental delay, refractory seizures, bilateral PNH, and perisylvian polymicrogyria. The other family members were less severely affected with mild developmental delay and isolated bilateral PNH. All family members had syndactyly. An unrelated patient presented with severe neurodevelopmental delay, seizures, and hypospadias, expanding the phenotypic spectrum. MRI revealed bilateral PNH and perisylvian polymicrogyria. All tested patients carry the recurrent variant c.623G > A, p.(Arg208Gln) in the WW domain of NEDD4L. The variant in the unrelated patient occurred de novo. This is the first report of a NEDD4L variant located in the WW domain which is probably involved in the recognition of substrates for ligation suggesting a loss of function variant.

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Morinda Officinalis Polysaccharides Inhibit Osteoclast Differentiation by Regulating miR-214-3p/NEDD4L in Postmenopausal Osteoporosis Mice

Huang,

Chen,

Lin

et al. 2024

Calcif Tissue Int

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To investigate the potential mechanism of Morinda officinalis F. C. How polysaccharides (MOPs) in regulating osteoclast differentiation and apoptosis through miR-214-3p and its target protein. Ovariectomy was performed in 8-week female C57BL6 mice to establish the postmenopausal osteoporosis (PMOP) model. Mice were treated immediately with 500 mg/kg of MOPs (prevention group); others were treated 2 weeks after operation (treatment group). Left femur bone mineral density (BMD) was examined. RAW264.7 cells were administered with receptor activator of NF-κB ligand (RANKL) to establish the osteoclast (OC) model and treated with serum containing 1 or 2 g/kg of MOPs. Apoptosis-related indexes, miR-214-3p, and Expressed Developmentally Down-regulated 4-Like (NEDD4L) were detected by western blot, quantitative real-time-reverse transcription polymerase chain reaction (qRT-PCR), and flow cytometry. OC received a miR-214-3p inhibitor or NEDD4L small interfering RNA (siRNA). MOPs reversed the PMOP-induced changes in bones. Compared with the RANKL group, MOPs increased the apoptosis and related markers in OCs. MOPs decreased the femur miR-214-3p of PMOP mice ( P < 0.001). Higher concentrations of MOPs reversed the upregulation of miR-214 mRNA in OCs ( P < 0.001). miR-214-3p inhibitor increased the expression of Bax and CC3 ( P < 0.01) and decreased the expression of Bcl-2 ( P < 0.05). NEDD4L is targeted by miR-214. NEDD4L was upregulated in the RANKL + MOPs group ( P < 0.01). miR-214-3p inhibitor increased the upregulation of NEDD4L induced by MOPs ( P < 0.05). siRNA NEDD4L significantly reversed the inhibition of MOPs on osteoclast differentiation with miR-214-3p inhibitor ( P < 0.01). MOPs effectively prevent PMOP by inhibiting osteoclastogenesis and inducing OC apoptosis through the miR-214-3p/NEDD4L pathway. Supplementary Information The online version contains supplementary material available at 10.1007/s00223-024-01271-8.

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Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli

Cited by 31 publications

References 41 publications

Identification of pain genes contributing to ciguatoxin-induced pain using haplotype-based computational genetic mapping in mice

Identification of pain genes contributing to ciguatoxin-induced pain using haplotype-based computational genetic mapping in mice

Recurrent NEDD4L Variant in Periventricular Nodular Heterotopia, Polymicrogyria and Syndactyly

Morinda Officinalis Polysaccharides Inhibit Osteoclast Differentiation by Regulating miR-214-3p/NEDD4L in Postmenopausal Osteoporosis Mice

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