A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial Segment

Zonta, Barbara; Desmazières, Anne; Rinaldi, Arianna; Tait, Steven; Sherman, Diane L.; Nolan, Matthew F.; Brophy, Peter

doi:10.1016/j.neuron.2011.02.021

Cited by 144 publications

(204 citation statements)

References 66 publications

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“…Loss of this important upstream anchor caused loss of neuronal polarity, a transition from axonal to dendritic identity and the formation of dendritic spines on the former axon (Hedstrom et al, 2008;Sobotzik et al, 2009). Additionally, recent evidence suggests that the cell-adhesion molecule Neurofascin186 is involved in the stabilization of the axon initial segment (Zonta et al, 2011). Finally, it has also been shown that the expression of a constitutively-active IKK increases spine density in neurons (Russo et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

König

Fenner

Byrne

et al. 2012

Journal of Cell Science

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SummaryNeuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-kB (NF-kB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/ FGF12), in the regulation of NF-kB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-kB modulator IKKc/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-kB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-kB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-kB activity in neurons.

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Section: Discussionmentioning

confidence: 99%

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

König

Fenner

Byrne

et al. 2012

Journal of Cell Science

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“…In this study, we aimed to validate a PRM-MS assay consisting of a panel of proteins presumed to be involved in processes regarding secretory vesicle functioning, synaptic functioning, and innate immunity [12][13][14][15][16][17][18][19][20][21]. Having performed a pilot study [29], in the present study, we investigated this panel in a larger and independent cohort that included subjects with MCI in addition to patients with AD dementia and control subjects.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, a decreased level in brain tissue and CSF of patients with AD compared with control subjects has also been described [27,28,40]. Studies on the role of NRXNs, NPTX1, NFASC, and NCANP in AD are rare, although the proteins have all been suggested to have a role in synapse formation, plasticity, and stability [17][18][19][20][21]. On the basis of using MS-based proteomics, CSF NRXN-1 has been found to be slightly decreased in patients with AD compared with control subjects in a small cohort of 16 subjects [36].…”

Section: Discussionmentioning

confidence: 99%

“…The PRM panel consisted of neurosecretory protein VGF (VGF), chromogranin A (CHGA), and secretogranin 2 (SCG2), granins that are presumed to be involved in axonal or synaptic vesicle transport (the granins VGF, CHGA, and SCG2) [12]; cystatin C (CysC), a protease involved in Aβ degradation [13,14]; β 2 -microglobulin (β 2 M) and lysozyme C (LysC), proteins involved in the innate immune system [15,16]; and neurexins (NRXNs) NRXN-1, NRXN-2, and NRXN-3 as well as neuronal pentraxin 1 (NPTX1), neurofascin (NFASC), and neurocan core protein (NCANP), proteins involved in synapse formation and stabilization [17][18][19][20][21]. Several of these proteins, including VGF, CHGA, SCG2, CysC, and β 2 M, have been suggested in previous studies to be involved in AD pathology [12][13][14][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

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Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

et al. 2018

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Background: We investigated whether a panel of 12 potential novel biomarkers consisting of proteins involved in synapse functioning and immunity would be able to distinguish patients with Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) from control subjects. Methods: We included 40 control subjects, 40 subjects with MCI, and 40 subjects with AD from the Amsterdam Dementia Cohort who were matched for age and sex (age 65 ± 5 years, 19 [48%] women). The mean follow-up of patients with MCI was 3 years. Two or three tryptic peptides per protein were analyzed in cerebrospinal fluid using parallel reaction monitoring mass spectrometry. Corresponding stable isotope-labeled peptides were added and used as reference peptides. Multilevel generalized estimating equations (GEEs) with peptides clustered per subject and per protein (as within-subject variables) were used to assess differences between diagnostic groups. To assess differential effects of individual proteins, we included the diagnosis × protein interaction in the model. Separate GEE analyses were performed to assess differences between stable patients and patients with progressive MCI (MCI-AD).Results: There was a main effect for diagnosis (p < 0.01) and an interaction between diagnosis and protein (p < 0.01). Analysis stratified according to protein showed higher levels in patients with MCI for most proteins, especially in patients with MCI-AD. Chromogranin A, secretogranin II, neurexin 3, and neuropentraxin 1 showed the largest effect sizes; β values ranged from 0.53 to 0.78 for patients with MCI versus control subjects or patients with AD, and from 0.67 to 0.98 for patients with MCI-AD versus patients with stable MCI. In contrast, neurosecretory protein VGF was lower in patients with AD than in patients with MCI (ß = −0.93 [SE 0.22]) and control subjects (ß = 0.46 [SE 0.19]). Conclusions: Our results suggest that several proteins involved in vesicular transport and synaptic stability are elevated in patients with MCI, especially in patients with MCI progressing to AD dementia. This may reflect early events in the AD pathophysiological cascade. These proteins may be valuable as disease stage or prognostic markers in an early symptomatic stage of the disease.

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“…NF186 is dispensable for the assembly of AIS and nodes Zonta et al 2008;Feinberg et al 2010), but is critical for the maintenance of the AIS (Zonta et al 2011), as well as of nodes in the PNS ) and the CNS (Desmazieres et al 2014). Interestingly, CNS nodes are more susceptible to disruption after genetic deletion of NF186 in adult mice than PNS nodes, an observation that likely reflects the major contribution of the PNJ in the CNS.…”

Section: Maintaining Excitable Domains In Myelinated Axonsmentioning

confidence: 98%

The Nodes of Ranvier: Molecular Assembly and Maintenance

Rasband

Peles

2015

Cold Spring Harb Perspect Biol

161

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Action potential (AP) propagation in myelinated nerves requires clustered voltage gated sodium and potassium channels. These channels must be specifically localized to nodes of Ranvier where the AP is regenerated. Several mechanisms have evolved to facilitate and ensure the correct assembly and stabilization of these essential axonal domains. This review highlights the current understanding of the axon intrinsic and glial extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the peripheral nervous system (PNS) and central nervous system (CNS).A xons conduct electrical signals, called action potentials (APs), among neurons in a circuit in response to sensory input, and between motor neurons and muscles. In mammals and other vertebrates, many axons are myelinated. Myelin, made by Schwann cells and oligodendrocytes in the peripheral nervous system (PNS) and central nervous system (CNS), respectively, is a multilamellar sheet of glial membrane that wraps around axons to increase transmembrane resistance and decrease membrane capacitance. Although myelin is traditionally viewed as a passive contributor to nervous system function, it is now recognized that myelinating glia also play many active roles including regulation of axon diameter, axonal energy metabolism, and the clustering of ion channels at gaps in the myelin sheath called nodes of Ranvier. Together, the active and passive properties conferred on axons by myelin, result in axons with high AP conduction velocities, low metabolic demands, and reduced space requirements as compared with unmyelinated axons. Thus, myelin and the clustering of ion channels in axons permitted the evolution of the complex nervous systems found in vertebrates. This review highlights the current understanding of the axonal intrinsic and glial extrinsic mechanisms that control the formation and maintenance of the nodes of Ranvier in both the PNS and CNS.

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A Critical Role for Neurofascin in Regulating Action Potential Initiation through Maintenance of the Axon Initial Segment

Cited by 144 publications

References 66 publications

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF-κB signaling in neurons

Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease

The Nodes of Ranvier: Molecular Assembly and Maintenance

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