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Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150 Deacetylation by Axonal HDAC1.
Pathak A, Stanley EM, Hickman FE, Wallace N, Brewer B, Li D, Gluska S, Perlson E, Fuhrmann S, Akassoglou K, Bronfman F, Casaccia P, Burnette DT, Carter BD
(2018) Dev Cell 46: 376-387.e7
MeSH Terms: Animals, Axonal Transport, Axons, Dynactin Complex, Histone Deacetylase 1, Microtubule-Associated Proteins, Neurons, Rats, Sprague-Dawley, Receptor, Nerve Growth Factor
Show Abstract · Added March 27, 2019
During development, neurons undergo apoptosis if they do not receive adequate trophic support from tissues they innervate or when detrimental factors activate the p75 neurotrophin receptor (p75NTR) at their axon ends. Trophic factor deprivation (TFD) or activation of p75NTR in distal axons results in a retrograde degenerative signal. However, the nature of this signal and the regulation of its transport are poorly understood. Here, we identify p75NTR intracellular domain (ICD) and histone deacetylase 1 (HDAC1) as part of a retrograde pro-apoptotic signal generated in response to TFD or ligand binding to p75NTR in sympathetic neurons. We report an unconventional function of HDAC1 in retrograde transport of a degenerative signal and its constitutive presence in sympathetic axons. HDAC1 deacetylates dynactin subunit p150, which enhances its interaction with dynein. These findings define p75NTR ICD as a retrograde degenerative signal and reveal p150 deacetylation as a unique mechanism regulating axonal transport.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
Cohen MR, Johnson WM, Pilat JM, Kiselar J, DeFrancesco-Lisowitz A, Zigmond RE, Moiseenkova-Bell VY
(2015) Mol Cell Biol 35: 4238-52
MeSH Terms: Animals, Calcium, Calcium Channels, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, HEK293 Cells, Humans, MAP Kinase Signaling System, Nerve Growth Factor, Neurites, Neurogenesis, Neurons, PC12 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, RNA Interference, RNA, Small Interfering, Rats, Receptor, trkA, TRPV Cation Channels, rab GTP-Binding Proteins
Show Abstract · Added April 24, 2017
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms
Genetic association signal near NTN4 in Tourette syndrome.
Paschou P, Yu D, Gerber G, Evans P, Tsetsos F, Davis LK, Karagiannidis I, Chaponis J, Gamazon E, Mueller-Vahl K, Stuhrmann M, Schloegelhofer M, Stamenkovic M, Hebebrand J, Noethen M, Nagy P, Barta C, Tarnok Z, Rizzo R, Depienne C, Worbe Y, Hartmann A, Cath DC, Budman CL, Sandor P, Barr C, Wolanczyk T, Singer H, Chou IC, Grados M, Posthuma D, Rouleau GA, Aschauer H, Freimer NB, Pauls DL, Cox NJ, Mathews CA, Scharf JM
(2014) Ann Neurol 76: 310-5
MeSH Terms: Adult, Case-Control Studies, Genome-Wide Association Study, Humans, Nerve Growth Factors, Netrins, Polymorphism, Single Nucleotide, Tourette Syndrome
Show Abstract · Added February 22, 2016
Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.
© 2014 American Neurological Association.
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8 MeSH Terms
Neurotrophic factors. Preface.
Lewin GR, Carter BD
(2014) Handb Exp Pharmacol 220: v-vi
MeSH Terms: Animals, Humans, Nerve Growth Factors
Added February 20, 2016
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3 MeSH Terms
A role for the p75 neurotrophin receptor in axonal degeneration and apoptosis induced by oxidative stress.
Kraemer BR, Snow JP, Vollbrecht P, Pathak A, Valentine WM, Deutch AY, Carter BD
(2014) J Biol Chem 289: 21205-16
MeSH Terms: Animals, Apoptosis, Axons, Cells, Cultured, Mice, Mice, Inbred C57BL, Oxidative Stress, Rats, Rats, Sprague-Dawley, Receptors, Nerve Growth Factor, Visual Field Tests
Show Abstract · Added January 22, 2015
The p75 neurotrophin receptor (p75(NTR)) mediates the death of specific populations of neurons during the development of the nervous system or after cellular injury. The receptor has also been implicated as a contributor to neurodegeneration caused by numerous pathological conditions. Because many of these conditions are associated with increases in reactive oxygen species, we investigated whether p75(NTR) has a role in neurodegeneration in response to oxidative stress. Here we demonstrate that p75(NTR) signaling is activated by 4-hydroxynonenal (HNE), a lipid peroxidation product generated naturally during oxidative stress. Exposure of sympathetic neurons to HNE resulted in neurite degeneration and apoptosis. However, these effects were reduced markedly in neurons from p75(NTR-/-) mice. The neurodegenerative effects of HNE were not associated with production of neurotrophins and were unaffected by pretreatment with a receptor-blocking antibody, suggesting that oxidative stress activates p75(NTR) via a ligand-independent mechanism. Previous studies have established that proteolysis of p75(NTR) by the metalloprotease TNFα-converting enzyme and γ-secretase is necessary for p75(NTR)-mediated apoptotic signaling. Exposure of sympathetic neurons to HNE resulted in metalloprotease- and γ-secretase-dependent cleavage of p75(NTR). Pharmacological blockade of p75(NTR) proteolysis protected sympathetic neurons from HNE-induced neurite degeneration and apoptosis, suggesting that cleavage of p75(NTR) is necessary for oxidant-induced neurodegeneration. In vivo, p75(NTR-/-) mice exhibited resistance to axonal degeneration associated with oxidative injury following administration of the neurotoxin 6-hydroxydopamine. Together, these data suggest a novel mechanism linking oxidative stress to ligand-independent cleavage of p75(NTR), resulting in axonal fragmentation and neuronal death.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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3 Members
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11 MeSH Terms
The biological functions and signaling mechanisms of the p75 neurotrophin receptor.
Kraemer BR, Yoon SO, Carter BD
(2014) Handb Exp Pharmacol 220: 121-64
MeSH Terms: Adaptor Proteins, Vesicular Transport, Animals, Apoptosis, Cell Cycle, Cell Survival, Humans, JNK Mitogen-Activated Protein Kinases, Myelin Sheath, NF-kappa B, Neuronal Plasticity, Protein Precursors, Receptor, Nerve Growth Factor, Receptor, trkA, Signal Transduction
Show Abstract · Added January 22, 2015
The p75 neurotrophin receptor (p75(NTR)) regulates a wide range of cellular functions, including programmed cell death, axonal growth and degeneration, cell proliferation, myelination, and synaptic plasticity. The multiplicity of cellular functions governed by the receptor arises from the variety of ligands and co-receptors which associate with p75(NTR) and regulate its signaling. P75(NTR) promotes survival through interactions with Trk receptors, inhibits axonal regeneration via partnerships with Nogo receptor (Nogo-R) and Lingo-1, and promotes apoptosis through association with Sortilin. Signals downstream of these interactions are further modulated through regulated intramembrane proteolysis (RIP) of p75(NTR) and by interactions with numerous cytosolic partners. In this chapter, we discuss the intricate signaling mechanisms of p75(NTR), emphasizing how these signals are differentially regulated to mediate these diverse cellular functions.
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14 MeSH Terms
The p75 neurotrophin receptor evades the endolysosomal route in neuronal cells, favouring multivesicular bodies specialised for exosomal release.
Escudero CA, Lazo OM, Galleguillos C, Parraguez JI, Lopez-Verrilli MA, Cabeza C, Leon L, Saeed U, Retamal C, Gonzalez A, Marzolo MP, Carter BD, Court FA, Bronfman FC
(2014) J Cell Sci 127: 1966-79
MeSH Terms: Animals, Endosomes, Exosomes, Lysosomes, Microscopy, Fluorescence, Multivesicular Bodies, Neurons, PC12 Cells, RNA Interference, Rats, Receptors, Nerve Growth Factor
Show Abstract · Added March 17, 2014
The p75 neurotrophin receptor (p75, also known as NGFR) is a multifaceted signalling receptor that regulates neuronal physiology, including neurite outgrowth, and survival and death decisions. A key cellular aspect regulating neurotrophin signalling is the intracellular trafficking of their receptors; however, the post-endocytic trafficking of p75 is poorly defined. We used sympathetic neurons and rat PC12 cells to study the mechanism of internalisation and post-endocytic trafficking of p75. We found that p75 internalisation depended on the clathrin adaptor protein AP2 and on dynamin. More surprisingly, p75 evaded the lysosomal route at the level of the early endosome, instead accumulating in two different types of endosomes, Rab11-positive endosomes and multivesicular bodies (MVBs) positive for CD63, a marker of the exosomal pathway. Consistently, depolarisation by KCl induced the liberation of previously endocytosed full-length p75 into the extracellular medium in exosomes. Thus, p75 defines a subpopulation of MVBs that does not mature to lysosomes and is available for exosomal release by neuronal cells.
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11 MeSH Terms
p75 neurotrophin receptor cleavage by α- and γ-secretases is required for neurotrophin-mediated proliferation of brain tumor-initiating cells.
Forsyth PA, Krishna N, Lawn S, Valadez JG, Qu X, Fenstermacher DA, Fournier M, Potthast L, Chinnaiyan P, Gibney GT, Zeinieh M, Barker PA, Carter BD, Cooper MK, Kenchappa RS
(2014) J Biol Chem 289: 8067-85
MeSH Terms: Amyloid Precursor Protein Secretases, Brain, Brain Neoplasms, Cell Line, Tumor, Cell Proliferation, Gene Knockdown Techniques, Glioma, Humans, Mutation, Neoplastic Stem Cells, Nerve Growth Factors, Receptor, Nerve Growth Factor
Show Abstract · Added March 17, 2014
Malignant gliomas are highly invasive, proliferative, and resistant to treatment. Previously, we have shown that p75 neurotrophin receptor (p75NTR) is a novel mediator of invasion of human glioma cells. However, the role of p75NTR in glioma proliferation is unknown. Here we used brain tumor-initiating cells (BTICs) and show that BTICs express neurotrophin receptors (p75NTR, TrkA, TrkB, and TrkC) and their ligands (NGF, brain-derived neurotrophic factor, and neurotrophin 3) and secrete NGF. Down-regulation of p75NTR significantly decreased proliferation of BTICs. Conversely, exogenouous NGF stimulated BTIC proliferation through α- and γ-secretase-mediated p75NTR cleavage and release of its intracellular domain (ICD). In contrast, overexpression of the p75NTR ICD induced proliferation. Interestingly, inhibition of Trk signaling blocked NGF-stimulated BTIC proliferation and p75NTR cleavage, indicating a role of Trk in p75NTR signaling. Further, blocking p75NTR cleavage attenuated Akt activation in BTICs, suggesting role of Akt in p75NTR-mediated proliferation. We also found that p75NTR, α-secretases, and the four subunits of the γ-secretase enzyme were elevated in glioblastoma multiformes patients. Importantly, the ICD of p75NTR was commonly found in malignant glioma patient specimens, suggesting that the receptor is activated and cleaved in patient tumors. These results suggest that p75NTR proteolysis is required for BTIC proliferation and is a novel potential clinical target.
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2 Members
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12 MeSH Terms
Genetics and diabetic retinopathy.
Schwartz SG, Brantley MA, Flynn HW
(2013) Curr Diabetes Rev 9: 86-92
MeSH Terms: Blindness, Diabetic Retinopathy, Disease Progression, Eye Proteins, Female, Genetic Predisposition to Disease, Glycation End Products, Advanced, Humans, Insulin-Like Growth Factor I, Male, Nerve Growth Factors, Protein Kinase C, Risk Factors, Serpins, Vascular Endothelial Growth Factor A
Show Abstract · Added February 23, 2017
There are many reasons to suspect a genetic influence on the development and progression of diabetic retinopathy, including substantial variability in disease severity among patients with similar risk factors. Linkage studies have suggested associations with chromosomes 1, 3, 12 and others. The most studied individual genes are those encoding vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products, all of which have shown statistically significant associations in multiple series from various parts of the world. At this time, no definite genetic associations with diabetic retinopathy have been consistently reported. This may be due to small sample sizes, differences in study design, underlying genetic differences between study populations, or other factors. As we continue to collect data, these relationships may become more clear.
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15 MeSH Terms
The SSRI citalopram affects fetal thalamic axon responsiveness to netrin-1 in vitro independently of SERT antagonism.
Bonnin A, Zhang L, Blakely RD, Levitt P
(2012) Neuropsychopharmacology 37: 1879-84
MeSH Terms: Animals, Axons, Citalopram, Coculture Techniques, Female, Fetus, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Transgenic, Nerve Growth Factors, Netrin-1, Paroxetine, Receptors, sigma, Serotonin, Serotonin Plasma Membrane Transport Proteins, Serotonin Uptake Inhibitors, Thalamus, Tumor Suppressor Proteins
Show Abstract · Added July 10, 2013
Serotonin (5-hydroxytryptamine, 5-HT) signaling is thought to modulate nervous system development. Genetic and pharmacological studies support the idea that altered 5-HT signaling during development can have enduring consequences on brain function and behavior. Recently, we discovered that 5-HT can modulate thalamic axon guidance in vitro and in vivo. Embryonic thalamic axons transiently express the 5-HT transporter (SERT; Slc6a4) and accumulate 5-HT, suggesting that the SERT activity of these axons may regulate 5-HT-modulated guidance cues. We tested whether pharmacologically blocking SERT using selective 5-HT reuptake inhibitors (SSRIs) would impact the action of 5-HT on thalamic axon responses to netrin-1 in vitro. Surprisingly, we observed that two high-affinity SSRIs, racemic citalopram ((RS)-CIT) and paroxetine, affect the outgrowth of embryonic thalamic axons, but differ with respect to their dependence on SERT blockade. Using a recently developed 'citalopram insensitive' transgenic mouse line and in vitro pharmacology, we show that the effect of (RS)-CIT effect is SERT independent, but rather arises from R-CIT activation of the orphan sigma-1 receptor(σ1, Oprs1). Our results reveal a novel σ1 activity in modulating axon guidance and a 5-HT independent action of a widely prescribed SSRI. By extension, (RS)-CIT and possibly other structurally similar SSRIs may have other off-target actions that can impact neural development and contribute to therapeutic efficacy or side effects.
2 Communities
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20 MeSH Terms