Journal articles on the topic 'P75NTR'
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1
Franco, María Luisa, Irmina García-Carpio, Raquel Comaposada-Baró, Juan J. Escribano-Saiz, Lucía Chávez-Gutiérrez, and Marçal Vilar. "TrkA-mediated endocytosis of p75-CTF prevents cholinergic neuron death upon γ-secretase inhibition." Life Science Alliance 4, no. 4 (February 3, 2021): e202000844. http://dx.doi.org/10.26508/lsa.202000844.
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γ-secretase inhibitors (GSI) were developed to reduce the generation of Aβ peptide to find new Alzheimer’s disease treatments. Clinical trials on Alzheimer’s disease patients, however, showed several side effects that worsened the cognitive symptoms of the treated patients. The observed side effects were partially attributed to Notch signaling. However, the effect on other γ-secretase substrates, such as the p75 neurotrophin receptor (p75NTR) has not been studied in detail. p75NTR is highly expressed in the basal forebrain cholinergic neurons (BFCNs) during all life. Here, we show that GSI treatment induces the oligomerization of p75CTF leading to the cell death of BFCNs, and that this event is dependent on TrkA activity. The oligomerization of p75CTF requires an intact cholesterol recognition sequence (CRAC) and the constitutive binding of TRAF6, which activates the JNK and p38 pathways. Remarkably, TrkA rescues from cell death by a mechanism involving the endocytosis of p75CTF. These results suggest that the inhibition of γ-secretase activity in aged patients, where the expression of TrkA in the BFCNs is already reduced, could accelerate cholinergic dysfunction and promote neurodegeneration.
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Marchetti, Laura, Fulvio Bonsignore, Francesco Gobbo, Rosy Amodeo, Mariantonietta Calvello, Ajesh Jacob, Giovanni Signore, et al. "Fast-diffusing p75NTR monomers support apoptosis and growth cone collapse by neurotrophin ligands." Proceedings of the National Academy of Sciences 116, no. 43 (September 12, 2019): 21563–72. http://dx.doi.org/10.1073/pnas.1902790116.
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The p75 neurotrophin (NT) receptor (p75NTR) plays a crucial role in balancing survival-versus-death decisions in the nervous system. Yet, despite 2 decades of structural and biochemical studies, a comprehensive, accepted model for p75NTR activation by NT ligands is still missing. Here, we present a single-molecule study of membrane p75NTR in living cells, demonstrating that the vast majority of receptors are monomers before and after NT activation. Interestingly, the stoichiometry and diffusion properties of the wild-type (wt) p75NTR are almost identical to those of a receptor mutant lacking residues previously believed to induce oligomerization. The wt p75NTR and mutated (mut) p75NTR differ in their partitioning in cholesterol-rich membrane regions upon nerve growth factor (NGF) stimulation: We argue that this is the origin of the ability of wt p75NTR , but not of mut p75NTR, to mediate immature NT (proNT)-induced apoptosis. Both p75NTR forms support proNT-induced growth cone retraction: We show that receptor surface accumulation is the driving force for cone collapse. Overall, our data unveil the multifaceted activity of the p75NTR monomer and let us provide a coherent interpretative frame of existing conflicting data in the literature.
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Klinger, Mary Beth, and Margaret A. Vizzard. "Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis." American Journal of Physiology-Renal Physiology 295, no. 6 (December 2008): F1778—F1789. http://dx.doi.org/10.1152/ajprenal.90501.2008.
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Previous studies demonstrated changes in urinary bladder neurotrophin content and upregulation of neurotrophin receptors, TrkA and the p75 neurotrophin receptor (p75NTR), in micturition reflex pathways after cyclophosphamide (CYP)-induced cystitis. p75NTR can bind nerve growth factor (NGF) and modulate NGF-TrkA binding and signaling. We examined p75NTR expression and the role of p75NTR in the micturition reflex in control and CYP-treated rats. p75NTR Immunoreactivity was present throughout the urinary bladder. CYP-induced cystitis (4 h, 48 h, chronic) increased ( P ≤ 0.05) p75NTR expression in whole urinary bladder as shown by Western blotting. The role of p75NTR in bladder function in control and CYP-treated rats was determined using conscious cystometry and immunoneutralization or PD90780, a compound known to specifically block NGF binding to p75NTR. An anti-p75NTR monoclonal antibody or PD90780 was infused intravesically and cystometric parameters were evaluated. Both methods of p75NTR blockade significantly ( P ≤ 0.05) decreased the intercontraction interval and void volume in control and CYP-treated rats. Intravesical infusion of PD90780 also significantly ( P ≤ 0.001) increased intravesical pressure and increased the number of nonvoiding contractions during the filling phase. Control intravesical infusions of isotype-matched IgG and vehicle were without effect. Intravesical instillation of PD90780 significantly ( P ≤ 0.01) reduced the volume threshold to elicit a micturition contraction in control rats (no inflammation) and CYP-treated in a closed urinary bladder system. These studies demonstrate 1) ubiquitous p75NTR expression in urinary bladder and increased expression with CYP-induced cystitis and 2) p75NTR blockade at the level of the urinary bladder produces bladder hyperreflexia in control and CYP-treated rats. The overall activity of the urinary bladder reflects the balance of NGF-p75NTR and NGF-TrkA signaling.
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Tan, Wei, Longjia Dong, Xuexing Shi, Qian Tang, and Dianming Jiang. "P75NTR Exacerbates SCI-induced Mitochondrial Damage and Neuronal Apoptosis Depending on NTRK3." Current Neurovascular Research 18, no. 5 (October 2021): 552–64. http://dx.doi.org/10.2174/1567202619666211231091834.
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Objective: The aim of the study was to investigate the mechanism by which p75 neurotrophin receptor (p75NTR) affects mitochondrial damage and neuronal apoptosis in spinal cord injury (SCI). Methods: After the establishment of SCI rat models, short hairpin (sh) RNA of p75NTR and control sh-RNA were injected into SCI rats, respectively. On days 1, 7 and 21 after SCI, the severity of SCI and cell apoptosis in SCI rats were determined as well as the recovery of hind limb performance and p75NTR expression. After spinal cord neurons were transfected with p75NTR overexpression plasmid or empty plasmid vector or cotransfected with overexpression plasmids of p75NTR and neurotrophic tyrosine receptor kinase3 (NTRK3), the expression levels of p75NTR and NTRK3 were quantified. Moreover, we detected the apoptosis and proliferation rates of the neurons in addition to the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) in the neurons. The binding between p75NTR and NTRK3 was confirmed via Co-immunoprecipitation (Co-IP). Results: The rat spinal cords in the Model group were notably damaged after SCI accompanied by increased apoptosis and decreased locomotor function. The expression of p75NTR was significantly upregulated after SCI. The aforementioned injuries were remarkably ameliorated in response to injection of sh-p75NTR. p75NTR overexpression induced mitochondrial damage and neuronal apoptosis in spinal cord neurons, while the promotive effects were perturbed by NTRK3 overexpression. Furthermore, p75NTR directly bound to and downregulated NTRK3. Conclusion: Both in vivo and in vitro experiments showed that p75NTR aggravates mitochondrial damage and neuronal apoptosis in SCI through downregulating NTRK3.
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Kenchappa, Rajappa, and Peter A. J. Forsyth. "Relationship of the p75 neurotrophin receptor (p75NTR) and hypoxic response and treatment resistance in malignant gliomas." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e13026-e13026. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13026.
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e13026 Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion & proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia & radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro & in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro & in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia & RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.
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Barrio, Tomás, Enric Vidal, Marina Betancor, Alicia Otero, Inmaculada Martín-Burriel, Marta Monzón, Eva Monleón, Martí Pumarola, Juan José Badiola, and Rosa Bolea. "Evidence of p75 Neurotrophin Receptor Involvement in the Central Nervous System Pathogenesis of Classical Scrapie in Sheep and a Transgenic Mouse Model." International Journal of Molecular Sciences 22, no. 5 (March 8, 2021): 2714. http://dx.doi.org/10.3390/ijms22052714.
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Neurotrophins constitute a group of growth factor that exerts important functions in the nervous system of vertebrates. They act through two classes of transmembrane receptors: tyrosine-kinase receptors and the p75 neurotrophin receptor (p75NTR). The activation of p75NTR can favor cell survival or apoptosis depending on diverse factors. Several studies evidenced a link between p75NTR and the pathogenesis of prion diseases. In this study, we investigated the distribution of several neurotrophins and their receptors, including p75NTR, in the brain of naturally scrapie-affected sheep and experimentally infected ovinized transgenic mice and its correlation with other markers of prion disease. No evident changes in infected mice or sheep were observed regarding neurotrophins and their receptors except for the immunohistochemistry against p75NTR. Infected mice showed higher abundance of p75NTR immunostained cells than their non-infected counterparts. The astrocytic labeling correlated with other neuropathological alterations of prion disease. Confocal microscopy demonstrated the co-localization of p75NTR and the astrocytic marker GFAP, suggesting an involvement of astrocytes in p75NTR-mediated neurodegeneration. In contrast, p75NTR staining in sheep lacked astrocytic labeling. However, digital image analyses revealed increased labeling intensities in preclinical sheep compared with non-infected and terminal sheep in several brain nuclei. This suggests that this receptor is overexpressed in early stages of prion-related neurodegeneration in sheep. Our results confirm a role of p75NTR in the pathogenesis of classical ovine scrapie in both the natural host and in an experimental transgenic mouse model.
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Majdan, Marta, Gregory S. Walsh, Raquel Aloyz, and Freda D. Miller. "TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal." Journal of Cell Biology 155, no. 7 (December 24, 2001): 1275–86. http://dx.doi.org/10.1083/jcb.200110017.
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Developmental sympathetic neuron death is determined by functional interactions between the TrkA/NGF receptor and the p75 neurotrophin receptor (p75NTR). A key question is whether p75NTR promotes apoptosis by directly inhibiting or modulating TrkA activity, or by stimulating cell death independently of TrkA. Here we provide evidence for the latter model. Specifically, experiments presented here demonstrate that the presence or absence of p75NTR does not alter Trk activity or NGF- and NT-3–mediated downstream survival signaling in primary neurons. Crosses of p75NTR−/− and TrkA−/− mice indicate that the coincident absence of p75NTR substantially rescues TrkA−/− sympathetic neurons from developmental death in vivo. Thus, p75NTR induces death regardless of the presence or absence of TrkA expression. These data therefore support a model where developing sympathetic neurons are “destined to die” by an ongoing p75NTR-mediated apoptotic signal, and one of the major ways that TrkA promotes neuronal survival is by silencing this ongoing death signal.
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Yang, Yaoli Pu, Simeng Wang, Xingguo Li, and Nina F. Schor. "Cell Line-Dependent Variability of Coordinate Expression of p75NTR and CRABP1 and Modulation of Effects of Fenretinide on Neuroblastoma Cells." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–8. http://dx.doi.org/10.1155/2016/7568287.
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Neuroblastoma is a childhood neural crest tumor. Fenretinide, a retinoic acid analogue, induces accumulation of mitochondrial reactive oxygen species and consequent apoptosis in neuroblastoma cells. The p75 neurotrophin receptor (p75NTR) enhances the antineuroblastoma cell efficacy of fenretinidein vitro. We examined the role of the retinoid binding protein, CRABP1, in p75NTR-mediated potentiation of the efficacy of fenretinide. Knockdown and overexpression, respectively, of either p75NTR or CRABP1 were effected in neuroblastoma cell lines using standard techniques. Expression was determined by qRT-PCR and confirmed at the protein level by Western blot. Metabolic viability was determined by Alamar blue assay. While protein content of CRABP1 correlated roughly with that of p75NTR in the three neuroblastoid or epithelioid human neuroblastoma cell lines studied, manipulation of p75NTR expression resulted in cell line-dependent, variable change in CRABP1 expression. Furthermore, in some cell lines, induced expression of CRABP1 in the absence of p75NTR did not alter cell sensitivity to fenretinide treatment. The effects of manipulation of p75NTR expression on CRABP1 expression and the effects of CRABP1 expression on fenretinide efficacy are therefore neuroblastoma cell line-dependent. Potentiation of the antineuroblastoma cell effects of fenretinide by p75NTR is not mediated solely through CRABP1.
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Triaca, Viviana, Elena Fico, Pamela Rosso, Massimo Ralli, Alessandro Corsi, Cinzia Severini, Alvaro Crevenna, et al. "Pilot Investigation on p75ICD Expression in Laryngeal Squamous Cell Carcinoma." Cancers 14, no. 11 (May 25, 2022): 2622. http://dx.doi.org/10.3390/cancers14112622.
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We investigated the p75 Neurotrophin Receptor (p75NTR) expression and cleavage product p75NTR Intracellular Domain (p75ICD) as potential oncogenic and metastatic markers in human Laryngeal Squamous Cell Carcinoma (LSCC). p75NTR is highly expressed in Cancer Stem Cells (CSCs) of the laryngeal epithelia and it has been proposed as a marker for stemness, cell migration, and chemo-resistance in different squamous carcinomas. To investigate the clinical significance of p75NTR cleavage products in solid tumors, full-length and cleaved p75NTR expression was analyzed in laryngeal primary tumors from different-stage LSCC patients, diagnosed at the Policlinico Umberto I Hospital. Molecular and histological techniques were used to detect the expressions of p75NTR and p75ICD, and ATP Binding Cassette Subfamily G Member 2 (ABCG2), a CSC marker. We found regulated p75NTR cleavage during squamous epithelial tumor progression and tissue invasion. Our preliminary investigation suggests p75ICD expression and localization as possible features of tumorigenesis and metastaticity. Its co-localization with ABCG2 in squamous cells in the parenchyma invaded by the tumor formation allows us to hypothesize p75NTR and p75ICD roles in tumor invasion and CSC spreading in LSCC patients. These data might represent a starting point for a comprehensive analysis of p75NTR cleavage and of its clinical relevance as a potential molecular LSCC signature, possibly helping diagnosis, and improving prognosis and personalized therapy.
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Tuffereau, Christine, Klaus Schmidt, Christelle Langevin, Florence Lafay, Georg Dechant, and Martin Koltzenburg. "The Rabies Virus Glycoprotein Receptor p75NTR Is Not Essential for Rabies Virus Infection." Journal of Virology 81, no. 24 (October 10, 2007): 13622–30. http://dx.doi.org/10.1128/jvi.02368-06.
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ABSTRACT Rabies virus glycoprotein (RVG) is known to be the only factor that mediates rabies infection. The neurotrophin receptor (p75NTR), through its cysteine-rich domain 1, is a specific receptor for RVG and neutralizes virus infectivity, but its role in virus infection has remained obscure. We used adult mouse dorsal root ganglion (DRG) neurons as a model to study the role of p75NTR in RV infection of primary neurons. We show that RV infects around 20% of DRG neurons, of which more than 80% are p75NTR positive, have large diameters, and are capsaicin insensitive. Surprisingly, RV binding and infection are absent in about half of the p75NTR-expressing DRG neurons which have small diameters and are often capsaicin sensitive. This indicates that p75NTR is not sufficient to mediate RV interaction in sensory neurons. The rate and specificity of neural infection are unchanged in RV-infected p75NTRExonIV−/− mice that lack all extracellular receptor domains and in wild-type mice infected with two independent RV mutants that lack p75NTR binding. Accordingly, the mortality rate is unchanged in the absence of RV-p75NTR interaction. We conclude that although p75NTR is a receptor for soluble RVG in transfected cells of heterologous expression systems, an RVG-p75NTR interaction is not necessary for RV infection of primary neurons. This means that other receptors are required to mediate RV infection in vivo and in vitro.
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Yamashita, Toshihide, Haruhisa Higuchi, and Masaya Tohyama. "The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho." Journal of Cell Biology 157, no. 4 (May 13, 2002): 565–70. http://dx.doi.org/10.1083/jcb.200202010.
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Myelin-associated glycoprotein (MAG) is a potent inhibitor of neurite outgrowth from a variety of neurons. The receptor for MAG or signals that elicit morphological changes in neurons remained to be established. Here we show that the neurotrophin receptor p75 (p75NTR) is the signal transducing element for MAG. Adult dorsal root ganglion neurons or postnatal cerebellar neurons from mice carrying a mutation in the p75NTR gene are insensitive to MAG with regard to neurite outgrowth. MAG activates small GTPase RhoA, leading to retarded outgrowth when p75NTR is present. Colocalization of p75NTR and MAG binding is seen in neurons. Ganglioside GT1b, which is one of the binding partners of MAG, specifically associates with p75NTR. Thus, p75NTR and GT1b may form a receptor complex for MAG to transmit the inhibitory signals in neurons.
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Lorentz, Christina U., Eric N. Alston, Todd Belcik, Jonathan R. Lindner, George D. Giraud, and Beth A. Habecker. "Heterogeneous ventricular sympathetic innervation, altered β-adrenergic receptor expression, and rhythm instability in mice lacking the p75 neurotrophin receptor." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 6 (June 2010): H1652—H1660. http://dx.doi.org/10.1152/ajpheart.01128.2009.
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Sympathetic nerves stimulate cardiac function through the release of norepinephrine and the activation of cardiac β1-adrenergic receptors. The sympathetic innervation of the heart is sculpted during development by chemoattractive factors including nerve growth factor (NGF) and the chemorepulsive factor semaphorin 3a. NGF acts through the TrkA receptor and the p75 neurotrophin receptor (p75NTR) in sympathetic neurons. NGF stimulates sympathetic axon extension into the heart through TrkA, but p75NTR modulates multiple coreceptors that can either stimulate or inhibit axon outgrowth. In mice lacking p75NTR, the sympathetic innervation density in target tissues ranges from denervation to hyperinnervation. Recent studies have revealed significant changes in the sympathetic innervation density of p75NTR-deficient (p75NTR−/−) atria between early postnatal development and adulthood. We examined the innervation of adult p75NTR−/− ventricles and discovered that the subendocardium of the p75NTR−/− left ventricle was essentially devoid of sympathetic nerve fibers, whereas the innervation density of the subepicardium was normal. This phenotype is similar to that seen in mice overexpressing semaphorin 3a, and we found that sympathetic axons lacking p75NTR are more sensitive to semaphorin 3a in vitro than control neurons. The lack of subendocardial innervation was associated with decreased dP/d t, altered cardiac β1-adrenergic receptor expression and sensitivity, and a significant increase in spontaneous ventricular arrhythmias. The lack of p75NTR also resulted in increased tyrosine hydroxylase content in cardiac sympathetic neurons and elevated norepinephrine in the right ventricle, where innervation density was normal.
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Perri, Anna, Vittoria Rago, Rocco Malivindi, Lorenza Maltese, Danilo Lofaro, Emanuela Alessandra Greco, Luigi Tucci, et al. "Overexpression of p75NTR in Human Seminoma: A New Biomarker?" Life 11, no. 7 (June 29, 2021): 629. http://dx.doi.org/10.3390/life11070629.
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Several studies have demonstrated that the p75NTR low-affinity receptor of Nerve Growth Factor (NGF), is produced in abnormally large amounts in several human cancer types. However, the role of p75NTR varies substantially depending on cell context, so that a dual role of this receptor protein in tumor cell survival and invasion, as well as cell death, has been supported in recent studies. Herein we explored for the first time the expression of p75NTR in human specimens (nr = 40) from testicular germ cell tumors (TGCTs), mostly seminomas. Nuclear overexpression of p75NTR was detected by immunohistochemistry in seminoma tissue as compared to normal tissue, whereas neither NGF nor its high-affinity TrkA receptor was detected. An increased nuclear staining of phospho-JNK, belonging to the p75NTR signaling pathway and its pro-apoptotic target gene, p53, was concomitantly observed. Interestingly, our analysis revealed that decreased expression frequency of p75NTR, p-JNK and p53 was related to staging progression, thus suggesting that p75NTR may represent a specific marker for seminoma and staging in TGCTs.
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Bamji, Shernaz X., Marta Majdan, Christine D. Pozniak, Daniel J. Belliveau, Raquel Aloyz, Judi Kohn, Carrie G. Causing, and Freda D. Miller. "The p75 Neurotrophin Receptor Mediates Neuronal Apoptosis and Is Essential for Naturally Occurring Sympathetic Neuron Death." Journal of Cell Biology 140, no. 4 (February 23, 1998): 911–23. http://dx.doi.org/10.1083/jcb.140.4.911.
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Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both the TrkA tyrosine kinase receptor and p75NTR. When sympathetic neuron survival is maintained with low quantities of NGF or KCl, the neurotrophin brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on sympathetic neurons, causes neuronal apoptosis and increased phosphorylation of c-jun. Function-blocking antibody studies indicate that this apoptosis is due to BDNF-mediated activation of p75NTR. To determine the physiological relevance of these culture findings, we examined sympathetic neurons in BDNF−/− and p75NTR−/− mice. In BDNF−/− mice, sympathetic neuron number is increased relative to BDNF+/+ littermates, and in p75NTR−/− mice, the normal period of sympathetic neuron death does not occur, with neuronal attrition occurring later in life. This deficit in apoptosis is intrinsic to sympathetic neurons, since cultured p75NTR−/− neurons die more slowly than do their wild-type counterparts. Together, these data indicate that p75NTR can signal to mediate apoptosis, and that this mechanism is essential for naturally occurring sympathetic neuron death.
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Lu, Qingli, Yuanyuan Qu, Yuan Ding, and Xiaojing Kang. "p75NTR/proBDNF Modulates Basal Cell Carcinoma (BCC) Immune Microenvironment via Necroptosis Signaling Pathway." Journal of Immunology Research 2021 (February 1, 2021): 1–10. http://dx.doi.org/10.1155/2021/6652846.
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Basal cell carcinoma (BCC) is the most common skin cancer. While most of the basal cell carcinomas were localized lesion and can be easily managed, the treatment options to the advanced basal cell carcinomas are still remarkably limited. In recent years, proBDNF and its receptor p75NTR have been reported to play important roles in various diseases, including cancers and psychotic disorders. However, the role of p75NTR/proBDNF signaling in basal cell carcinoma remains unclear. Here, we found that the expression level of p75NTR/proBDNF was decreased in basal cell carcinoma patient samples and cell lines. In vitro study showed overexpression of p75NTR/proBDNF could significantly facilitate tumor cell death, including inflammatory-silent apoptosis and lytic inflammatory activated necroptosis. In vivo study showed overexpression of p75NTR/proBDNF dramatically promotes tumor-associated macrophage (M1) and T cell recruitment in a syngeneic mouse model of BCC. These results show a crucial role for p75NTR/proBDNF signaling in basal cell carcinoma immune microenvironment.
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Deshpande, Sachin S., Subash C. Malik, Pasquale Conforti, Jia-di Lin, Yu-Hsuan Chu, Suvra Nath, Franziska Greulich, Meike-Ast Dumbach, N. Henriette Uhlenhaut, and Christian Schachtrup. "P75 neurotrophin receptor controls subventricular zone neural stem cell migration after stroke." Cell and Tissue Research 387, no. 3 (October 26, 2021): 415–31. http://dx.doi.org/10.1007/s00441-021-03539-z.
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AbstractStroke is the leading cause of adult disability. Endogenous neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to the brain repair process. However, molecular mechanisms underlying CNS disease-induced SVZ NSPC-redirected migration to the lesion area are poorly understood. Here, we show that genetic depletion of the p75 neurotrophin receptor (p75NTR−/−) in mice reduced SVZ NSPC migration towards the lesion area after cortical injury and that p75NTR−/− NSPCs failed to migrate upon BDNF stimulation in vitro. Cortical injury rapidly increased p75NTR abundance in SVZ NSPCs via bone morphogenetic protein (BMP) receptor signaling. SVZ-derived p75NTR−/− NSPCs revealed an altered cytoskeletal network- and small GTPase family-related gene and protein expression. In accordance, BMP-treated non-migrating p75NTR−/− NSPCs revealed an altered morphology and α-tubulin expression compared to BMP-treated migrating wild-type NSPCs. We propose that BMP-induced p75NTR abundance in NSPCs is a regulator of SVZ NSPC migration to the lesion area via regulation of the cytoskeleton following cortical injury.
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Li, HongMei, HuiLi Shi, and KeKe Huo. "p75NTR signal transduction suppressed by BFAR and p75NTR interactions." Science China Life Sciences 55, no. 4 (April 2012): 367–74. http://dx.doi.org/10.1007/s11427-012-4306-y.
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Xu, Minlin, Carmelle V. Remillard, Benjamin D. Sachs, Ayako Makino, Oleksandr Platoshyn, Weijuan Yao, Wolfgang H. Dillmann, Katerina Akassoglou, and Jason X. J. Yuan. "p75 neurotrophin receptor regulates agonist-induced pulmonary vasoconstriction." American Journal of Physiology-Heart and Circulatory Physiology 295, no. 4 (October 2008): H1529—H1538. http://dx.doi.org/10.1152/ajpheart.00115.2008.
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A member of the TNF receptor family, the p75 neurotrophin receptor (p75NTR) has been previously shown to play a role in the regulation of fibrin deposition in the lung. However, the role of p75NTR in the regulation of pulmonary vascular tone in the lung is unknown. In the present study, we evaluated the expression of p75NTR in mouse pulmonary arteries and the putative role of p75NTR in modulating pulmonary vascular tone and agonist responsiveness using wild-type (WT) and p75NTR knockout (p75−/−) mice. Our data indicated that p75NTR is expressed in both smooth muscle and endothelial cells within the pulmonary vascular wall in WT mice. Pulmonary artery rings from p75−/− mice exhibited significantly elevated active tension due to endothelin-1-mediated Ca2+ influx. Furthermore, the contraction due to capacitative Ca2+ entry (CCE) in response to phenylephrine-mediated active depletion of intracellular Ca2+ stores was significantly enhanced compared with WT rings. The contraction due to CCE induced by passive store depletion, however, was comparable between WT and p75−/− rings. Active tension induced by serotonin, U-46619 (a thromboxane A2 analog), thrombin, 4-aminopyridine (a K+ channel blocker), and high extracellular K+ in p75−/− rings was similar to that in WT rings. Deletion of p75NTR did not alter pulmonary vasodilation to sodium nitroprusside (a nitric oxide donor). These data suggest that intact p75NTR signaling may play a role in modulating pulmonary vasoconstriction induced by endothelin-1 and by active store depletion.
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Becker, Kathrin, Armend Cana, Wolfgang Baumgärtner, and Ingo Spitzbarth. "p75 Neurotrophin Receptor: A Double-Edged Sword in Pathology and Regeneration of the Central Nervous System." Veterinary Pathology 55, no. 6 (June 25, 2018): 786–801. http://dx.doi.org/10.1177/0300985818781930.
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The low-affinity nerve growth factor receptor p75NTR is a major neurotrophin receptor involved in manifold and pleiotropic functions in the developing and adult central nervous system (CNS). Although known for decades, its entire functions are far from being fully elucidated. Depending on the complex interactions with other receptors and on the cellular context, p75NTR is capable of performing contradictory tasks such as mediating cell death as well as cell survival. In parallel, as a prototype marker for certain differentiation stages of Schwann cells and related CNS aldynoglial cells, p75NTR has recently gained increasing notice as a marker for cells with proposed regenerative potential in CNS diseases, such as demyelinating disease and traumatic CNS injury. Besides its pivotal role as a marker for transplantation candidate cells, recent studies in canine neuroinflammatory CNS conditions also highlight a spontaneous endogenous occurrence of p75NTR-positive glia, which potentially play a role in Schwann cell–mediated CNS remyelination. The aim of the present communication is to review the pleiotropic functions of p75NTR in the CNS with a special emphasis on its role as an immunohistochemical marker in neuropathology. Following a brief illustration of the expression of p75NTR in neurogenesis and in developed neuronal populations, the implications of p75NTR expression in astrocytes, oligodendrocytes, and microglia are addressed. A special focus is put on the role of p75NTR as a cell marker for specific differentiation stages of Schwann cells and a regeneration-promoting CNS population, collectively referred to as aldynoglia.
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PERRONE, Lorena, Simona PALADINO, Marialuisa MAZZONE, Lucio NITSCH, Massimo GULISANO, and Chiara ZURZOLO. "Functional interaction between p75NTR and TrkA: the endocytic trafficking of p75NTR is driven by TrkA and regulates TrkA-mediated signalling." Biochemical Journal 385, no. 1 (December 14, 2004): 233–41. http://dx.doi.org/10.1042/bj20041155.
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The topology and trafficking of receptors play a key role in their signalling capability. Indeed, receptor function is related to the microenvironment inside the cell, where specific signalling molecules are compartmentalized. The response to NGF (nerve growth factor) is strongly dependent on the trafficking of its receptor, TrkA. However, information is still scarce about the role of the cellular localization of the TrkA co-receptor, p75NTR (where NTR is neurotrophin receptor), following stimulation by NGF. It has been shown that these two receptors play a key role in epithelial tissue and in epithelial-derived tumours, where the microenvironment at the plasma membrane is defined by the presence of tight junctions. Indeed, in thyroid carcinomas, rearrangements of TrkA are frequently found, which produce TrkA mutants that are localized exclusively in the cytoplasm. We used a thyroid cellular model in which it was possible to dissect the trafficking of the two NGF receptors upon neurotrophin stimulation. In FRT (Fischer rat thyroid) cells, endogenous TrkA is localized exclusively on the basolateral surface, while transfected p75NTR is selectively distributed on the apical membrane. This cellular system enabled us to selectively stimulate either p75NTR or TrkA and to analyse the role of receptor trafficking in their signalling capability. We found that, after binding to NGF, p75NTR was co-immunoprecipitated with TrkA and was transcytosed at the basolateral membrane. We showed that the TrkA–p75NTR interaction is necessary for this relocation of p75NTR to the basolateral side. Interestingly, TrkA-specific stimulation by basolateral NGF loading also induced the TrkA–p75NTR interaction and subsequent p75NTR transcytosis at the basolateral surface. Moreover, specific stimulation of p75NTR by NGF activated TrkA and the MAPK (mitogen-activated protein kinase) pathway. Our data indicate that TrkA regulates the subcellular localization of p75NTR upon stimulation with neurotrophins, thus affecting the topology of the signal transduction molecules, driving the activation of a specific signal transduction pathway.
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Sycheva, Marina, Jake Sustarich, Yuxian Zhang, Vaithinathan Selvaraju, Thangiah Geetha, Marla Gearing, and Jeganathan Ramesh Babu. "Pro-Nerve Growth Factor Induces Activation of RhoA Kinase and Neuronal Cell Death." Brain Sciences 9, no. 8 (August 19, 2019): 204. http://dx.doi.org/10.3390/brainsci9080204.
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We have previously shown that the expression of pro-nerve growth factor (proNGF) was significantly increased, nerve growth factor (NGF) level was decreased, and the expression of p75NTR was enhanced in Alzheimer’s disease (AD) hippocampal samples. NGF regulates cell survival and differentiation by binding TrkA and p75NTR receptors. ProNGF is the precursor form of NGF, binds to p75NTR, and induces cell apoptosis. The objective of this study is to determine whether the increased p75NTR expression in AD is due to the accumulation of proNGF and Rho kinase activation. PC12 cells were stimulated with either proNGF or NGF. Pull-down assay was carried out to determine the RhoA kinase activity. We found the expression of p75NTR was enhanced by proNGF compared to NGF. The proNGF stimulation also increased the RhoA kinase activity leading to apoptosis. The expression of active RhoA kinase was found to be increased in human AD hippocampus compared to control. The addition of RhoA kinase inhibitor Y27632 not only blocked the RhoA kinase activity but also reduced the expression of p75NTR receptor and inhibited the activation of JNK and MAPK induced by proNGF. This suggests that overexpression of proNGF in AD enhances p75NTR expression and activation of RhoA, leading to neuronal cell death.
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Montroull, Laura E., Deborah E. Rothbard, Hur D. Kanal, Veera D’Mello, Vincent Dodson, Carol M. Troy, Juan P. Zanin, Steven W. Levison, and Wilma J. Friedman. "Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice." ASN Neuro 12 (January 2020): 175909142093086. http://dx.doi.org/10.1177/1759091420930865.
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The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.
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Costantini, Claudio, Richard Weindruch, Giuliano Della Valle, and Luigi Puglielli. "A TrkA-to-p75NTR molecular switch activates amyloid β-peptide generation during aging." Biochemical Journal 391, no. 1 (September 26, 2005): 59–67. http://dx.doi.org/10.1042/bj20050700.
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Aging is the single most important risk factor for AD (Alzheimer's disease). However, the molecular events that connect normal aging to AD are mostly unknown. The abnormal accumulation of Aβ (amyloid β-peptide) in the form of senile plaques is one of the main characteristics of AD. In the present study, we show that two members of the neurotrophin receptor superfamily, TrkA (tyrosine kinase receptor A) and p75NTR (p75 neurotrophin receptor), differentially regulate the processing of APP (amyloid precursor protein): TrkA reduces, whereas p75NTR activates, β-cleavage of APP. The p75NTR-dependent effect requires NGF (nerve growth factor) binding and activation of the second messenger ceramide. We also show that normal aging activates Aβ generation in the brain by ‘switching’ from the TrkA to the p75NTR receptor system. Such an effect is abolished in p75NTR ‘knockout’ animals, and can be blocked by both caloric restriction and inhibitors of nSMase (neutral sphingomyelinase). In contrast with caloric restriction, which prevents the age-associated up-regulation of p75NTR expression, nSMase inhibitors block the activation of ceramide. When taken together, these results indicate that the p75NTR–ceramide signalling pathway activates the rate of Aβ generation in an age-dependent fashion, and provide a new target for both the understanding and the prevention of late-onset AD.
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Subirada, Paula Virginia, Albana Tovo, María Victoria Vaglienti, José Domingo Luna Pinto, Horacio Uri Saragovi, Maria Cecilia Sánchez, Agustín Anastasía, and Pablo Federico Barcelona. "Etiological Roles of p75NTR in a Mouse Model of Wet Age-Related Macular Degeneration." Cells 12, no. 2 (January 12, 2023): 297. http://dx.doi.org/10.3390/cells12020297.
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Choroidal neovascularization (CNV) is a pathological angiogenesis of the choroidal plexus of the retina and is a key feature in the wet form of age-related macular degeneration. Mononuclear phagocytic cells (MPCs) are known to accumulate in the subretinal space, generating a chronic inflammatory state that promotes the growth of the choroidal neovasculature. However, how the MPCs are recruited and activated to promote CNV pathology is not fully understood. Using genetic and pharmacological tools in a mouse model of laser-induced CNV, we demonstrate a role for the p75 neurotrophin receptor (p75NTR) in the recruitment of MPCs, in glial activation, and in vascular alterations. After laser injury, expression of p75NTR is increased in activated Muller glial cells near the CNV area in the retina and the retinal pigmented epithelium (RPE)-choroid. In p75NTR knockout mice (p75NTR KO) with CNV, there is significantly reduced recruitment of MPCs, reduced glial activation, reduced CNV area, and the retinal function is preserved, as compared to wild type mice with CNV. Notably, a single intravitreal injection of a pharmacological p75NTR antagonist in wild type mice with CNV phenocopied the results of the p75NTR KO mice. Our results demonstrate that p75NTR is etiological in the development of CNV.
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Dunay, Ildiko Rita, Rainer Hellweg, Björn H. Schott, Golo Kronenberg, Ulrike Schmidt, Henning P. Düsedau, Stefanie Ehrentraut, Olga Geisel, Oliver von Bohlen und Halbach, and Peter Gass. "Robustly High Hippocampal BDNF levels under Acute Stress in Mice Lacking the Full-length p75 Neurotrophin Receptor." Pharmacopsychiatry 54, no. 05 (February 16, 2021): 205–13. http://dx.doi.org/10.1055/a-1363-1680.
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ABSTRACT Background Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation. Method We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTRExIII−/−) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 (Il6) was assessed with RT-PCR. Results Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain Il6 mRNA expression irrespective of genotype; however, p75NTRExIII−/− mice showed elevated baseline Il6 expression and thus a lower relative increase. Conclusions Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related Il6 gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.
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Dedoni, Simona, Luisa Marras, Maria C. Olianas, Angela Ingianni, and Pierluigi Onali. "Valproic acid upregulates the expression of the p75NTR/sortilin receptor complex to induce neuronal apoptosis." Apoptosis 25, no. 9-10 (July 25, 2020): 697–714. http://dx.doi.org/10.1007/s10495-020-01626-0.
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Abstract The antiepileptic and mood stabilizer agent valproic acid (VPA) has been shown to exert anti-tumour effects and to cause neuronal damage in the developing brain through mechanisms not completely understood. In the present study we show that prolonged exposure of SH-SY5Y and LAN-1 human neuroblastoma cells to clinically relevant concentrations of VPA caused a marked induction of the protein and transcript levels of the common neurotrophin receptor p75NTR and its co-receptor sortilin, two promoters of apoptotic cell death in response to proneurotrophins. VPA induction of p75NTR and sortilin was associated with an increase in plasma membrane expression of the receptor proteins and was mimicked by cell treatment with several histone deacetylase (HDAC) inhibitors. VPA and HDAC1 knockdown decreased the level of EZH2, a core component of the polycomb repressive complex 2, and upregulated the transcription factor CASZ1, a positive regulator of p75NTR. CASZ1 knockdown attenuated VPA-induced p75NTR overexpression. Cell treatment with VPA favoured proNGF-induced p75NTR/sortilin interaction and the exposure to proNGF enhanced JNK activation and apoptotic cell death elicited by VPA. Depletion of p75NTR or addition of the sortilin agonist neurotensin to block proNGF/sortilin interaction reduced the apoptotic response to VPA and proNGF. Exposure of mouse cerebellar granule cells to VPA upregulated p75NTR and sortilin and induced apoptosis which was enhanced by proNGF. These results indicate that VPA upregulates p75NTR apoptotic cell signalling through an epigenetic mechanism involving HDAC inhibition and suggest that this effect may contribute to the anti-neuroblastoma and neurotoxic effects of VPA.
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Castellini, Cesare, Simona Mattioli, Elisa Cotozzolo, Alessandra Pistilli, Mario Rende, Desirée Bartolini, Gabriele Di Sante, Laura Menchetti, Alessandro Dal Bosco, and Anna Maria Stabile. "The Effect of Interaction NGF/p75NTR in Sperm Cells: A Rabbit Model." Cells 11, no. 6 (March 18, 2022): 1035. http://dx.doi.org/10.3390/cells11061035.
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Background: Nerve Growth Factor (NGF) plays an important role in the reproductive system through its receptor’s interaction (p75NTR). This paper aims to analyze the impact of NGF p75NTR in epididymal and ejaculated rabbit semen during in vitro sperm storage. Methods: Semen samples from 10 adult rabbit bucks were collected four times (n = 40) and analyzed. NGF was quantified in seminal plasma, and the basal expression of p75NTR in sperm was established (time 0). Moreover, we evaluated p75NTR, the apoptotic rates, and the main sperm parameters, at times 2–4 and 6 h with or without the administration of exogenous NGF. Results: Based on the level of p75NTR, we defined the threshold value (25.6%), and sperm were divided into High (H) and Normal (N). During sperm storage, p75NTR of H samples significantly modulated some relevant sperm parameters. Specifically, comparing H samples with N ones, we observed a reduction in motility and non-capacitated cell number, together with an increased percentage of dead and apoptotic cells. Notably, the N group showed a reduction in dead and apoptotic cells after NGF treatment. Conversely, the NGF administration on H sperm did not change either the percentage of dead cells or the apoptotic rate. Conclusion: The concentration of p75NTR on ejaculated sperm modulates many semen outcomes (motility, apoptosis, viability) through NGF interaction affecting the senescence of sperm.
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Choi, Soyoung, and Wilma J. Friedman. "Inflammatory Cytokines IL-1β and TNF-α Regulate p75NTR Expression in CNS Neurons and Astrocytes by Distinct Cell-Type-Specific Signalling Mechanisms." ASN Neuro 1, no. 2 (April 22, 2009): AN20090009. http://dx.doi.org/10.1042/an20090009.
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The p75NTR (where NTR is neurotrophin receptor) can mediate many distinct cellular functions, including cell survival and apoptosis, axonal growth and cell proliferation, depending on the cellular context. This multifunctional receptor is widely expressed in the CNS (central nervous system) during development, but its expression is restricted in the adult brain. However, p75NTR is induced by a variety of pathophysiological insults, including seizures, lesions and degenerative disease. We have demonstrated previously that p75NTR is induced by seizures in neurons, where it induces apoptosis, and in astrocytes, where it may regulate proliferation. In the present study, we have investigated whether the inflammatory cytokines IL (interleukin)-1 β and TNF- α (tumour necrosis factor- α), that are commonly elevated in these pathological conditions, mediate the regulation of p75NTR in neurons and astrocytes. We have further analysed the signal transduction pathways by which these cytokines induce p75NTR expression in the different cell types, specifically investigating the roles of the NF- κB (nuclear factor κB) and p38 MAPK (mitogen-activated protein kinase) pathways. We have demonstrated that both cytokines regulate p75NTR expression; however, the mechanisms governing this regulation are cytokine- and cell-type specific. The distinct mechanisms of cytokine-mediated p75NTR regulation that we demonstrate in the present study may facilitate therapeutic intervention in regulation of this receptor in a cell-selective manner.
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Elshaer, Sally L., Hang-soo Park, Laura Pearson, William D. Hill, Frank M. Longo, and Azza B. El-Remessy. "Modulation of p75NTR on Mesenchymal Stem Cells Increases Their Vascular Protection in Retinal Ischemia-Reperfusion Mouse Model." International Journal of Molecular Sciences 22, no. 2 (January 15, 2021): 829. http://dx.doi.org/10.3390/ijms22020829.
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Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and receiving LM11A-31 was assessed by visual-clue water-maze test. I/R significantly increased the number of acellular capillaries (3.2-Fold) in WT retinas, which was partially ameliorated in p75NTR-/- retinas. GFP-MSCs were successfully incorporated and engrafted into retinal vasculature 1 week post injection and normalized the number of acellular capillaries in p75NTR-/- retinas, yet ischemic WT retinas maintained a 2-Fold increase. Silencing p75NTR on GFP-MSCs coincided with a higher number of cells homing to the ischemic WT retinal vasculature and normalized the number of acellular capillaries when compared to ischemic WT retinas receiving scrambled-GFP-MSCs. In vitro, silencing p75NTR-MSCs enhanced their secretome, as evidenced by significant increases in SDF-1, VEGF and NGF release in MSCs conditioned medium; improved paracrine angiogenic response in HREs, where HREs showed enhanced migration (1.4-Fold) and tube formation (2-Fold) compared to controls. In parallel, modulating MSCs-p75NTR using LM11A-31 resulted in a similar improvement in MSCs secretome and the enhanced paracrine angiogenic potential of HREs. Further, intervention with LM11A-31 significantly mitigated the decline in visual acuity post retinal I/R injury. In conclusion, p75NTR modulation can potentiate the therapeutic potential of MSCs to harness vascular repair in ischemic retinopathy diseases.
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Yang, Li-Na, Wen-Kai Huang, Xue-Li Li, Yu-Zuo Bai, and Shu-Cheng Zhang. "Sox10 Is a Specific Biomarker for Neural Crest Stem Cells in Immunohistochemical Staining in Wistar Rats." Disease Markers 2020 (August 30, 2020): 1–7. http://dx.doi.org/10.1155/2020/8893703.
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Objective. Neural crest stem cells (NCSCs) are prototypically migratory cells immigrating from the dorsal neural tube to specific embryonic sites where they generate a variety of cell types. A lot of biomarkers for NCSCs have been identified. However, which biomarkers are the most specific is still unclear. Methods. The rat embryos harvested in embryonic day 9 (E9), E9.5, E10, E10.5, E11, E12, E13, and E14 were paraffin-embedded and sectioned in transverse. NCSCs were spatiotemporally demonstrated by immunohistochemical staining with RET, p75NTR, Pax7, and Sox10. NCSCs were isolated, cultured, and stained with RET, p75NTR, Pax7, and Sox10. Results. In the paraffin sections of rat embryos, the immunohistochemical staining of RET, p75NTR, and Sox10 can all be used in demonstrating NCSCs. Sox10 was positive mainly in NCSCs while RET and p75NTR were positive not only in NCSCs but also in other tissue cells. In primary culture cells, Sox10 was mainly in the nucleus of NCSCs, RET was mainly in the membrane, and p75NTR was positive in cytoplasm and membrane. Conclusions. Sox10 is the specific marker for immunohistochemical staining of NCSCs in paraffin sections. In cultured cells, Sox10, p75NTR, and RET presented a similar staining effect.
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Sachs, Benjamin D., George S. Baillie, Julianne R. McCall, Melissa A. Passino, Christian Schachtrup, Derek A. Wallace, Allan J. Dunlop, et al. "p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway." Journal of Cell Biology 177, no. 6 (June 18, 2007): 1119–32. http://dx.doi.org/10.1083/jcb.200701040.
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Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury.
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Siao, Chia-Jen, Christina U. Lorentz, Pouneh Kermani, Tina Marinic, John Carter, Kelly McGrath, Victoria A. Padow, et al. "ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation." Journal of Experimental Medicine 209, no. 12 (October 22, 2012): 2291–305. http://dx.doi.org/10.1084/jem.20111749.
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Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro–nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75NTR) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75NTR in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75NTR by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75NTR in proNGF-expressing mice rescues the phenotype, confirming the importance of p75NTR-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75NTR limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.
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Wang, Haitao, Rikang Wang, Thilini Thrimawithana, Peter J. Little, Jiangping Xu, Zhong-Ping Feng, and Wenhua Zheng. "The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/759473.
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Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC’s survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma.
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Dubreuil, Catherine I., Matthew J. Winton, and Lisa McKerracher. "Rho activation patterns after spinal cord injury and the role of activated Rho in apoptosis in the central nervous system." Journal of Cell Biology 162, no. 2 (July 8, 2003): 233–43. http://dx.doi.org/10.1083/jcb.200301080.
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Growth inhibitory proteins in the central nervous system (CNS) block axon growth and regeneration by signaling to Rho, an intracellular GTPase. It is not known how CNS trauma affects the expression and activation of RhoA. Here we detect GTP-bound RhoA in spinal cord homogenates and report that spinal cord injury (SCI) in both rats and mice activates RhoA over 10-fold in the absence of changes in RhoA expression. In situ Rho-GTP detection revealed that both neurons and glial cells showed Rho activation at SCI lesion sites. Application of a Rho antagonist (C3–05) reversed Rho activation and reduced the number of TUNEL-labeled cells by ∼50% in both injured mouse and rat, showing a role for activated Rho in cell death after CNS injury. Next, we examined the role of the p75 neurotrophin receptor (p75NTR) in Rho signaling. After SCI, an up-regulation of p75NTR was detected by Western blot and observed in both neurons and glia. Treatment with C3–05 blocked the increase in p75NTR expression. Experiments with p75NTR-null mutant mice showed that immediate Rho activation after SCI is p75NTR dependent. Our results indicate that blocking overactivation of Rho after SCI protects cells from p75NTR-dependent apoptosis.
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Kuo, Min-Hsun, Hung-Fu Lee, Yi-Fang Tu, Li-Hsuan Lin, Ya-Yun Cheng, and Hsueh-Te Lee. "Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains." International Journal of Molecular Sciences 20, no. 24 (December 6, 2019): 6168. http://dx.doi.org/10.3390/ijms20246168.
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Ischemic stroke is a leading cause of human death in present times. Two phases of pathological impact occur during an ischemic stroke, namely, ischemia and reperfusion. Both periods include individual characteristic effects on cell injury and apoptosis. Moreover, these conditions can cause severe cell defects and harm the blood-brain barrier (BBB). Also, the BBB components are the major targets in ischemia-reperfusion injury. The BBB owes its enhanced protective roles to capillary endothelial cells, which maintain BBB permeability. One of the nerve growth factor (NGF) receptors initiating cell signaling, once activated, is the p75 neurotrophin receptor (p75NTR). This receptor is involved in both the survival and apoptosis of neurons. Although many studies have attempted to explain the role of p75NTR in neurons, the mechanisms in endothelial cells remain unclear. Endothelial cells are the first cells to encounter p75NTR stimuli. In this study, we found the upregulated p75NTR expression and reductive expression of tight junction proteins after in vivo and in vitro ischemia-reperfusion injury. Moreover, astaxanthin (AXT), an antioxidant drug, was utilized and was found to reduce p75NTR expression and the number of apoptotic cells. This study verified that p75NTR plays a prominent role in endothelial cell death and provides a novel downstream target for AXT.
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Dedoni, Simona, Alessandra Olianas, Barbara Manconi, Maria Collu, Barbara Tuveri, Maria Elena Vincis, Maria C. Olianas, and Pierluigi Onali. "Upregulation of p75NTR by Histone Deacetylase Inhibitors Sensitizes Human Neuroblastoma Cells to Targeted Immunotoxin-Induced Apoptosis." International Journal of Molecular Sciences 23, no. 7 (March 31, 2022): 3849. http://dx.doi.org/10.3390/ijms23073849.
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Histone deacetylase (HDAC) inhibitors are novel chemotherapy agents with potential utility in the treatment of neuroblastoma, the most frequent solid tumor of childhood. Previous studies have shown that the exposure of human neuroblastoma cells to some HDAC inhibitors enhanced the expression of the common neurotrophin receptor p75NTR. In the present study we investigated whether the upregulation of p75NTR could be exploited to render neuroblastoma cells susceptible to the cytotoxic action of an anti-p75NTR antibody conjugated to the toxin saporin-S6 (p75IgG-Sap). We found that two well-characterized HDAC inhibitors, valproic acid (VPA) and entinostat, were able to induce a strong expression of p75NTR in different human neuroblastoma cell lines but not in other cells, with entinostat, displaying a greater efficacy than VPA. Cell pretreatment with entinostat enhanced p75NTR internalization and intracellular saporin-S6 delivery following p75IgG-Sap exposure. The addition of p75IgG-Sap had no effect on vehicle-pretreated cells but potentiated the apoptotic cell death that was induced by entinostat. In three-dimensional neuroblastoma cell cultures, the subsequent treatment with p75IgG-Sap enhanced the inhibition of spheroid growth and the impairment of cell viability that was produced by entinostat. In athymic mice bearing neuroblastoma xenografts, chronic treatment with entinostat increased the expression of p75NTR in tumors but not in liver, kidney, heart, and cerebellum. The administration of p75IgG-Sap induced apoptosis only in tumors of mice that were pretreated with entinostat. These findings define a novel experimental strategy to selectively eliminate neuroblastoma cells based on the sequential treatment with entinostat and a toxin-conjugated anti-p75NTR antibody.
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Yeaman, Charles, Annick H. Le Gall, Anne N. Baldwin, Laure Monlauzeur, Andre Le Bivic, and Enrique Rodriguez-Boulan. "The O-glycosylated Stalk Domain Is Required for Apical Sorting of Neurotrophin Receptors in Polarized MDCK Cells." Journal of Cell Biology 139, no. 4 (November 17, 1997): 929–40. http://dx.doi.org/10.1083/jcb.139.4.929.
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Delivery of newly synthesized membrane-spanning proteins to the apical plasma membrane domain of polarized MDCK epithelial cells is dependent on yet unidentified sorting signals present in the luminal domains of these proteins. In this report we show that structural information for apical sorting of transmembrane neurotrophin receptors (p75NTR) is localized to a juxtamembrane region of the extracellular domain that is rich in O-glycosylated serine/threonine residues. An internal deletion of 50 amino acids that removes this stalk domain from p75NTR causes the protein to be sorted exclusively of the basolateral plasma membrane. Basolateral sorting stalk-minus p75NTR does not occur by default, but requires sequences present in the cytoplasmic domain. The stalk domain is also required for apical secretion of a soluble form of p75NTR, providing the first demonstration that the same domain can mediate apical sorting of both a membrane-anchored as well as secreted protein. However, the single N-glycan present on p75NTR is not required for apical sorting of either transmembrane or secreted forms.
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Sissoëff, Ludmilla, Mohamed Mousli, Patrick England, and Christine Tuffereau. "Stable trimerization of recombinant rabies virus glycoprotein ectodomain is required for interaction with the p75NTR receptor." Journal of General Virology 86, no. 9 (September 1, 2005): 2543–52. http://dx.doi.org/10.1099/vir.0.81063-0.
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Native rabies virus glycoprotein (RVGvir) is a trimeric, membrane-anchored protein that has been shown to interact with the p75NTR neurotrophin receptor. In order to determine if the RVG trimeric oligomerization state is required for its binding with p75NTR, different soluble recombinant molecules containing the entire RVG ectodomain (RVGect) were expressed alone or fused at its C terminus to the trimerization domain of the bacteriophage T4 fibritin, termed ‘foldon’. The oligomerization status of recombinant RVG was investigated using sedimentation in sucrose gradient and p75NTR binding assays. It was found that, in the absence of the fibritin foldon, recombinant RVGect forms unstable trimers that dissociate into monomers in a concentration-dependent manner. C-terminal fusion with the foldon induces stable RVG trimerization, which is concentration-independent. Furthermore, the fibritin foldon maintains the native antigenic structure of the carboxy part of RVGect. Cell binding experiments showed that RVG trimerization is required for efficient interaction with p75NTR. However, the exact mode of trimerization appears unimportant, as trimeric recombinant RVGect (fused to the fibritin foldon) and RVGvir both recognize p75NTR with similar nanomolar affinities, as shown by surface plasmon resonance experiments. Altogether, these results show that the C-terminal fusion of the RVG ectodomain with the fibritin foldon is a powerful way to obtain a recombinant trimeric native-like structure of the p75NTR binding domain of RVG.
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Stary, Creed M., Xiaoyun Sun, and Rona G. Giffard. "Astrocytes Protect against Isoflurane Neurotoxicity by Buffering pro-brain–derived Neurotrophic Factor." Anesthesiology 123, no. 4 (October 1, 2015): 810–19. http://dx.doi.org/10.1097/aln.0000000000000824.
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Abstract Background: Isoflurane induces cell death in neurons undergoing synaptogenesis via increased production of pro-brain–derived neurotrophic factor (proBDNF) and activation of postsynaptic p75 neurotrophin receptor (p75NTR). Astrocytes express p75NTR, but their role in neuronal p75NTR-mediated cell death remains unclear. The authors investigated whether astrocytes have the capacity to buffer increases in proBDNF and protect against isoflurane/p75NTR neurotoxicity. Methods: Cell death was assessed in day in vitro (DIV) 7 mouse primary neuronal cultures alone or in co-culture with age-matched or DIV 21 astrocytes with propidium iodide 24 h after 1 h exposure to 2% isoflurane or recombinant proBDNF. Astrocyte-targeted knockdown of p75NTR in co-culture was achieved with small-interfering RNA and astrocyte-specific transfection reagent and verified with immunofluorescence microscopy. proBDNF levels were assessed by enzyme-linked immunosorbent assay. Each experiment used six to eight replicate cultures/condition and was repeated at least three times. Results: Exposure to isoflurane significantly (P < 0.05) increased neuronal cell death in primary neuronal cultures (1.5 ± 0.7 fold, mean ± SD) but not in co-culture with DIV 7 (1.0 ± 0.5 fold) or DIV 21 astrocytes (1.2 ± 1.2 fold). Exogenous proBDNF dose dependently induced neuronal cell death in both primary neuronal and co-cultures, an effect enhanced by astrocyte p75NTR inhibition. Astrocyte-targeted p75NTR knockdown in co-cultures increased media proBDNF (1.2 ± 0.1 fold) and augmented isoflurane-induced neuronal cell death (3.8 ± 3.1 fold). Conclusions: The presence of astrocytes provides protection to growing neurons by buffering increased levels of proBDNF induced by isoflurane. These findings may hold clinical significance for the neonatal and injured brain where increased levels of proBDNF impair neurogenesis.
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Devarajan, Shine, and Jeya Sundara Sharmila. "Computational Studies of Beta Amyloid (Aβ42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer’s Disease." Advances in Bioinformatics 2014 (November 11, 2014): 1–6. http://dx.doi.org/10.1155/2014/736378.
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Alzheimer’s disease is a neurodegenerative disorder characterized by the accumulation of beta amyloid plaques (Aβ) which can induce neurite degeneration and progressive dementia. It has been identified that neuronal apoptosis is induced by binding of Aβ42 to pan neurotrophin receptor (p75NTR) and gave the possibility that beta amyloid oligomer is a ligand for p75NTR. However, the atomic contact point responsible for molecular interactions and conformational changes of the protein upon binding was not studied in detail. In view of this, we conducted a molecular docking and simulation study to investigate the binding behaviour of Aβ42 monomer with p75NTR ectodomain. Furthermore, we proposed a p75NTR-ectodomain-Aβ42 complex model. Our data revealed that, Aβ42 specifically recognizes CRD1 and CRD2 domains of the receptor and formed a “cap” like structure at the N-terminal of receptor which is stabilized by a network of hydrogen bonds. These findings are supported by molecular dynamics simulation that Aβ42 showed distinct structural alterations at N- and C-terminal regions due to the influence of the receptor binding site. Overall, the present study gives more structural insight on the molecular interactions of beta amyloid protein involved in the activation of p75NTR receptor.
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Rogez, Bernadette, Quentin Pascal, Audrey Bobillier, François Machuron, Robert-Alain Toillon, Dominique Tierny, Valérie Chopin, and Xuefen Le Bourhis. "Expression and Prognostic Significance of Neurotrophins and Their Receptors in Canine Mammary Tumors." Veterinary Pathology 57, no. 4 (April 30, 2020): 507–19. http://dx.doi.org/10.1177/0300985820921813.
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Accumulating data highlight the role of neurotrophins and their receptors in human breast cancer. This family includes nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both synthetized as proneurotrophins (proNGF and proBDNF). (pro)NGF and (pro)BDNF initiate their biological effects by binding to both their specific receptors TrkA and TrkB, respectively, and the common receptor p75NTR. Currently, no data are available about their expression and potential role in canine mammary tumors. The aim of this study was to investigate expression of proNGF and BDNF as well as their receptors TrkA, TrkB, and p75NTR in canine mammary carcinomas, and to correlate them with clinicopathological parameters (grade, histological type, lymph node status, recurrence, and distant metastasis) and survival. Immunohistochemistry was performed on serial sections of 96 canine mammary carcinomas with antibodies against proNGF, BDNF, TrkA, TrkB, and p75NTR. Of the 96 carcinomas, proNGF expression was detected in 71 (74%), BDNF in 79 (82%), TrkA in 94 (98%), TrkB in 35 (37%), and p75NTR in 44 (46%). No association was observed between proNGF, BDNF, or TrkA expression and either clinicopathological parameters or survival. TrkB and p75NTR expression were associated with favorable clinicopathological parameters as well as better overall survival.
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Yang, Yaoli Pu, Louis Lotta, Gisela Beutner, Xingguo Li, and Nina F. Schor. "Induction of Expression of p75 Neurotrophin Receptor Intracellular Domain Does Not Induce Expression or Enhance Activity of Mitochondrial Complex II." Oxidative Medicine and Cellular Longevity 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/8752821.
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Fenretinide is a chemotherapeutic agent in clinical trials for the treatment of neuroblastoma, among the most common and most deadly cancers of childhood. Fenretinide induces apoptosis in neuroblastoma cells through accumulation of mitochondrial reactive oxygen species released from Complex II. The neurotrophin receptor, p75NTR, potentiates this effect. The signaling activity of p75NTR is dependent upon its cleavage to its intracellular domain, p75ICD, trafficking of p75ICD to the nucleus, and functioning of p75ICD as a transcription factor. Mitochondrial Complex II comprises 4 subunits, all of which are encoded by nuclear DNA. We therefore hypothesized that the fenretinide-potentiating effects of p75NTR are the result of transcriptional enrichment of Complex II by p75ICD. However, the present studies demonstrate that neither induced expression of p75ICD or its active fragments nor overexpression of p75NTR results in altered expression or activity of Complex II.
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Herrmann, J. L., D. G. Menter, J. Hamada, D. Marchetti, M. Nakajima, and G. L. Nicolson. "Mediation of NGF-stimulated extracellular matrix invasion by the human melanoma low-affinity p75 neurotrophin receptor: melanoma p75 functions independently of trkA." Molecular Biology of the Cell 4, no. 11 (November 1993): 1205–16. http://dx.doi.org/10.1091/mbc.4.11.1205.
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Although overexpression of the low-affinity p75 neurotrophin receptor (p75NTR) is frequently associated with advanced stages of human melanoma progression, the functional significance of this finding is unknown. We examined whether the degree of cell surface expression of p75NTR in human melanoma cell variants determines their extent of invasion stimulated by nerve growth factor (NGF). Treatment of MeWo melanoma cells or a metastatic spontaneous wheat germ agglutinin-resistant variant subline (70W) of MeWo cells with 2.5S NGF resulted in a dose-dependent enhancement of invasion through a reconstituted basement membrane. This effect was most pronounced with the 70W subline that exhibits brain-metastasizing potential in nude mice but was not found with a poorly metastatic MeWo variant subline (3S5). The expression of p75NTR as determined by Northern blotting and immunoprecipitation analysis of 125I-labeled cell surface proteins correlated with NGF-stimulated invasion. The MeWo melanoma sublines used in this study did not express p140proto-trkA mRNA or any p140proto-trkA variant transcripts including p70trkA as determined by Northern analysis and RT-PCR analysis. Thus, these melanoma cells would not be expected to form functional p75-p140 heterodimers or p140-p140 homodimers capable of transducing an NGF-generated signal to p140proto-trkA cytoplasmic substrates. These cells did express authentic p145trkC transcripts. However, NGF did not catalytically activate p145trkC receptors via increased tyrosine phosphorylation as would be expected if p145trkC participated in the signaling established by NGF. Furthermore, a NGF-stimulated purine-analogue-sensitive kinase activity was found to coimmunoprecipitate with p75NTR. This p75NTR-associated kinase may coordinate initial signaling events evoked by p75NTR ligand interaction. Addition of 2.5S NGF, at concentrations that should saturate cell surface p75NTR, to matrix-adherent cultures of human MeWo and 70W but not 3S5 melanoma cells suppressed the expression of 92-kDa type IV collagenase and stimulated the production of 72-kDa type IV collagenase in its fully active 68-kDa form. In the absence of p140proto-trkA, the matrix-dependent effects of NGF on metalloproteinase expression of brain-metastatic 70W melanoma cells suggest a signaling role for the low-affinity melanoma p75NTR receptor and its associated purine-analogue-sensitive kinase in signaling enhanced matrix penetration of NGF-rich stromal microenvironments such as the brain.
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Dees, W. Les, J. K. Hiney, N. H. McArthur, G. A. Johnson, G. A. Dissen, and S. R. Ojeda. "Origin and Ontogeny of Mammalian Ovarian Neurons." Endocrinology 147, no. 8 (August 1, 2006): 3789–96. http://dx.doi.org/10.1210/en.2006-0394.
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Mammalian ovaries contain sympathetic neurons expressing the low affinity neurotropin receptor (p75NTR). To date neither the role these neurons might play in ovarian physiology nor their embryological origin is known. Immunohistochemistry was used to detect postnatal changes in distribution and number of both p75NTR-positive and tyrosine hydroxylase-positive neurons in rhesus monkey ovaries. Pig fetuses were used to map the pathway of ovarian neuronal migration during embryonic development. Antiserum to p75NTR revealed the presence of isolated neurons and neurons clustered into ganglia in 2-month-old monkey ovaries. After 8 months, the neurons exhibited well-developed processes, and other than being more extensively interlaced, the localization and morphology did not change after 2 yr of age. Total number of p75NTR-positive neurons present decreased gradually between 2 months and 12 yr of age and declined markedly with reproductive aging. Conversely, the subpopulation of neurons immunoreactive to anti-tyrosine hydroxylase increased significantly at puberty and then declined with the loss of reproductive capacity. By d 21 of fetal life in the pig, p75NTR neurons had migrated medially from the neural crest to form the paraaortic autonomic ganglia. Some neurons migrated ventrally from the ganglia and then continued ventrolaterally to enter the genital ridge. By d 27, neurons had entered the developing ovary, and by d 35, the migration was complete with neurons demonstrating immunoreactivity to NeuN, a neuron-specific marker. Results demonstrate that p75NTR-expressing ovarian neurons originate from the neural crest and that a catecholaminergic subset is associated with pubertal maturation of the ovary and subsequent reproductive function.
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Perini, Giovanni, Vittorina Della-Bianca, Valeria Politi, Giuliano Della Valle, Ilaria Dal-Pra, Filippo Rossi, and Ubaldo Armato. "Role of p75 Neurotrophin Receptor in the Neurotoxicity by β-amyloid Peptides and Synergistic Effect of Inflammatory Cytokines." Journal of Experimental Medicine 195, no. 7 (April 1, 2002): 907–18. http://dx.doi.org/10.1084/jem.20011797.
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The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of β-amyloid peptides (Aβ), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75NTR) is responsible for neuronal damage by interacting with Aβ. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75NTR, we could show that p75NTR is involved in the direct signaling of cell death by Aβ via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Aβ could act synergistically. In fact, TNF-α and IL-1β, cytokines produced by Aβ-activated microglia, could potentiate the neurotoxic action of Aβ mediated by p75NTR signaling. Together, our results indicate that neurons expressing p75NTR, mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Aβ in AD.
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Tuffereau, Christine, Emmanuel Desmézières, Jacqueline Bénéjean, Corinne Jallet, Anne Flamand, Noël Tordo, and Pierre Perrin. "Interaction of lyssaviruses with the low-affinity nerve-growth factor receptor p75NTR." Journal of General Virology 82, no. 12 (December 1, 2001): 2861–67. http://dx.doi.org/10.1099/0022-1317-82-12-2861.
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The low-affinity nerve-growth factor receptor p75NTR interacts in vitro with the rabies virus (RV) glycoprotein and serves as a receptor for RV. The Lyssavirus genus comprises seven genotypes (GTs) of rabies and rabies-related viruses. The ability of p75NTR to interact with the glycoprotein of representative lyssaviruses from each GT was investigated. This investigation was based on a specific binding assay between BSR cells infected with a lyssavirus and Spodoptera frugiperda (Sf21) cells expressing p75NTR on the cell surface. A specific interaction was observed with the glycoprotein of GT 1 RV (challenge virus standard or Pasteur virus strains) as well as wild-type RV and the glycoprotein of GT 6 European bat lyssavirus type 2. In contrast, no interaction was detected with the glycoprotein of lyssaviruses of GTs 2–5 and 7. Therefore, p75NTR is only a receptor for some lyssavirus glycoproteins, indicating that the other GTs must use an alternative specific receptor.
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Venkatesh, Karthik, Onanong Chivatakarn, Shey-Shing Sheu, and Roman J. Giger. "Molecular dissection of the myelin-associated glycoprotein receptor complex reveals cell type–specific mechanisms for neurite outgrowth inhibition." Journal of Cell Biology 177, no. 3 (April 30, 2007): 393–99. http://dx.doi.org/10.1083/jcb.200702102.
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Neuronal Nogo66 receptor-1 (NgR1) binds the myelin inhibitors NogoA, OMgp, and myelin-associated glycoprotein (MAG) and has been proposed to function as the ligand-binding component of a receptor complex that also includes Lingo-1, p75NTR, or TROY. In this study, we use Vibrio cholerae neuraminidase (VCN) and mouse genetics to probe the molecular composition of the MAG receptor complex in postnatal retinal ganglion cells (RGCs). We find that VCN treatment is not sufficient to release MAG inhibition of RGCs; however, it does attenuate MAG inhibition of cerebellar granule neurons. Furthermore, the loss of p75NTR is not sufficient to release MAG inhibition of RGCs, but p75NTR−/− dorsal root ganglion neurons show enhanced growth on MAG compared to wild-type controls. Interestingly, TROY is not a functional substitute for p75NTR in RGCs. Finally, NgR1−/− RGCs are strongly inhibited by MAG. In the presence of VCN, however, NgR1−/− RGCs exhibit enhanced neurite growth. Collectively, our experiments reveal distinct and cell type–specific mechanisms for MAG-elicited growth inhibition.
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Zhou, Xin-Fu, and Yan-Jiang Wang. "The p75NTR extracellular domain." Prion 5, no. 3 (July 2011): 161–63. http://dx.doi.org/10.4161/pri.5.3.16896.
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Gough, N. R. "Transcription Factor for p75NTR." Science Signaling 2, no. 57 (February 10, 2009): ec47-ec47. http://dx.doi.org/10.1126/scisignal.257ec47.
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Barker, Philip A. "p75NTR Is Positively Promiscuous." Neuron 42, no. 4 (May 2004): 529–33. http://dx.doi.org/10.1016/j.neuron.2004.04.001.
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