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1.
Cell Mol Life Sci ; 79(1): 24, 2021 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-34966948

RESUMO

Protecting neurons from death during oxidative and neuroexcitotoxic stress is key for preventing cognitive dysfunction. We uncovered a novel neuroprotective mechanism involving interaction between neurotrophic factor-α1 (NF-α1/carboxypeptidase E, CPE) and human 5-HTR1E, a G protein-coupled serotonin receptor with no previously known neurological function. Co-immunoprecipitation and pull-down assays confirmed interaction between NFα1/CPE and 5-HTR1E and 125I NF-α1/CPE-binding studies demonstrated saturable, high-affinity binding to 5-HTR1E in stably transfected HEK293 cells (Kd = 13.82 nM). Treatment of 5-HTR1E stable cells with NF-α1/CPE increased pERK 1/2 and pCREB levels which prevented a decrease in pro-survival protein, BCL2, during H2O2-induced oxidative stress. Cell survival assay in ß-arrestin Knockout HEK293 cells showed that the NF-α1/CPE-5-HTR1E-mediated protection against oxidative stress was ß-arrestin-dependent. Molecular dynamics studies revealed that NF-α1/CPE interacts with 5-HTR1E via 3 salt bridges, stabilized by several hydrogen bonds, independent of the serotonin pocket. Furthermore, after phosphorylating the C-terminal tail and intracellular loop 3 (ICL3) of NF-α1/CPE-5-HTR1E, it recruited ß-arrestin1 by forming numerous salt bridges and hydrogen bonds to ICL2 and ICL3, leading to activation of ß-arrestin1. Immunofluorescence studies showed 5-HTR1E and NF-α1/CPE are highly expressed and co-localized on cell surface of human hippocampal neurons. Importantly, knock-down of 5-HTR1E in human primary neurons diminished the NF-α1/CPE-mediated protection of these neurons against oxidative stress and glutamate neurotoxicity-induced cell death. Thus, NF-α1/CPE uniquely interacts with serotonin receptor 5-HTR1E to activate the ß-arrestin/ERK/CREB/BCL2 pathway to mediate stress-induced neuroprotection.


Assuntos
Carboxipeptidase H/metabolismo , Sistema de Sinalização das MAP Quinases , Fatores de Crescimento Neural/metabolismo , Neurônios/metabolismo , Neurotoxinas/toxicidade , Estresse Oxidativo , Receptores de Serotonina/metabolismo , beta-Arrestinas/metabolismo , Animais , Carboxipeptidase H/química , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação para Baixo/efeitos dos fármacos , Células HEK293 , Hipocampo/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Receptores de Serotonina/química
2.
PLoS Pathog ; 17(10): e1009967, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34648590

RESUMO

Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1ß release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during Yersinia infection, we identified a line of Card19-deficient mice (Card19lxcn) whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as an independently-generated CRISPR/Cas9 Card19 knockout mouse line (Card19Null) showed no defect in macrophage cell lysis. Notably, Card19 is located on chromosome 13, immediately adjacent to Ninj1, which was recently found to regulate cell lysis downstream of GSDMD activation. RNA-seq and western blotting revealed that Card19lxcn BMDMs have significantly reduced NINJ1 expression, and reconstitution of Ninj1 in Card19lxcn immortalized BMDMs restored their ability to undergo cell lysis in response to caspase-dependent cell death stimuli. Card19lxcn mice exhibited increased susceptibility to Yersinia infection, whereas independently-generated Card19Null mice did not, demonstrating that cell lysis itself plays a key role in protection against bacterial infection, and that the increased infection susceptibility of Card19lxcn mice is attributable to loss of NINJ1. Our findings identify genetic targeting of Card19 being responsible for off-target effects on the adjacent gene Ninj1, disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during Yersinia infection.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Macrófagos/metabolismo , Fatores de Crescimento Neural/metabolismo , Yersiniose/patologia , Animais , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Piroptose/fisiologia , Yersiniose/metabolismo
3.
Mol Pharmacol ; 100(5): 491-501, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34470776

RESUMO

The neurotrophin growth factors bind and activate two types of cell surface receptors: the tropomyosin receptor kinase (Trk) family and p75. TrkA, TrkB, and TrkC are bound preferentially by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (NT3), respectively, to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins, and paradoxically in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D) or to reduce p75 binding (mutant RK). We also combined these features in a molecule that activates TrkA, TrkB, and TrkC but has reduced p75 binding (mutant DRK). In neurodegenerative disease mouse models in vivo, the DRK protein is a superior therapeutic agent compared with mutant D, mutant RK, and wild-type neurotrophins and protects a broader range of stressed neurons. This work rationalizes a therapeutic strategy based on the biology of each type of receptor, avoiding activation of p75 toxicity while broadly activating neuroprotection in stressed neuronal populations expressing different Trk receptors. SIGNIFICANCE STATEMENT: The neurotrophins nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 each can activate a tropomyosin receptor kinase (Trk) A, TrkB, or TrkC receptor, respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.


Assuntos
Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuroproteção/fisiologia , Engenharia de Proteínas/métodos , Receptor trkA/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Animais , Axotomia/efeitos adversos , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/metabolismo , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Fatores de Crescimento Neural/administração & dosagem , Fatores de Crescimento Neural/genética , Proteínas do Tecido Nervoso/genética , Neuroproteção/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/metabolismo , Receptor trkA/genética , Receptores de Fatores de Crescimento/genética
4.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576177

RESUMO

Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.


Assuntos
Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Microscopia Confocal , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/genética , Ratos , Proteínas Recombinantes/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Ácido gama-Aminobutírico/metabolismo
5.
Adv Exp Med Biol ; 1331: 289-307, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453307

RESUMO

Neurotrophins are evolutionary well-conserved molecules, and fish constitute valuable vertebrate models to explore their pleiotropic role in the brain. In addition to an introduction on the evolutionary importance of using fish in biomedicine and their neuroanatomy in comparison with mammals, here we review the available literature on the molecular evolution of neurotrophins and their receptors in teleost fish as well as their role in the fish brain, from the early stages of development until adulthood and aging. Among neurotrophins, BDNF is the most well studied in the brain of teleost fish, and we report data on the functional involvement of the BDNF/TrkB system in the development of the visual system and in the mechanisms of adult brain regeneration. With the exception of neuroanatomical expression, much less is known about the role of the other members of neurotrophin family in fish brain. We hope that this chapter opens new avenues leading to a better understanding of the complex and multifaceted roles of neurotrophins in the brain of fish and other vertebrates.


Assuntos
Encéfalo , Fatores de Crescimento Neural , Animais , Encéfalo/metabolismo , Evolução Molecular , Peixes/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Vertebrados/metabolismo
6.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445312

RESUMO

"Neuroplasticity" is often evoked to explain adaptation and compensation after acute lesions of the Central Nervous System (CNS). In this study, we investigated the modification of 80 genes involved in synaptic plasticity at different times (24 h, 8 and 45 days) from the traumatic spinal cord injury (SCI), adopting a bioinformatic analysis. mRNA expression levels were analyzed in the motor cortex, basal ganglia, cerebellum and in the spinal segments rostral and caudal to the lesion. The main results are: (i) a different gene expression regulation is observed in the Spinal Cord (SC) segments rostral and caudal to the lesion; (ii) long lasting changes in the SC includes the extracellular matrix (ECM) enzymes Timp1, transcription regulators (Egr, Nr4a1), second messenger associated proteins (Gna1, Ywhaq); (iii) long-lasting changes in the Motor Cortex includes transcription regulators (Cebpd), neurotransmitters/neuromodulators and receptors (Cnr1, Gria1, Nos1), growth factors and related receptors (Igf1, Ntf3, Ntrk2), second messenger associated proteins (Mapk1); long lasting changes in Basal Ganglia and Cerebellum include ECM protein (Reln), growth factors (Ngf, Bdnf), transcription regulators (Egr, Cebpd), neurotransmitter receptors (Grin2c). These data suggest the molecular mapping as a useful tool to investigate the brain and SC reorganization after SCI.


Assuntos
Encéfalo/metabolismo , Plasticidade Neuronal/genética , Traumatismos da Medula Espinal/metabolismo , Medula Espinal/metabolismo , Transcriptoma , Animais , Feminino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurotransmissores/genética , Neurotransmissores/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/genética , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
7.
Sci Rep ; 11(1): 14462, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262056

RESUMO

Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. As targeting of transcription factors is challenging, we tested whether modulation of REST activity could be achieved through knockdown of carboxy-terminal domain small phosphatase 1 (CTDSP1), the enzyme that stabilizes REST by preventing its targeting to the proteasome. To test whether knockdown of CTDSP1 promotes neurotrophic factor expression in both support cells located at the site of injury and in peripheral neurons, we transfected mesenchymal progenitor cells (MPCs), a type of support cells that are present at high concentrations at the site of injury, and dorsal root ganglion (DRG) neurons with REST or CTDSP1 specific siRNA. We quantified neurotrophic factor expression by RT-qPCR and Western blot, and brain-derived neurotrophic factor (BDNF) release in the cell culture medium by ELISA, and we measured neurite outgrowth of DRG neurons in culture. Our results show that CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs, and promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may, therefore, represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.


Assuntos
Regeneração Nervosa/fisiologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Fosfoproteínas Fosfatases/genética , Proteínas Repressoras/metabolismo , Animais , Axônios/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Gânglios Espinais/citologia , Gânglios Espinais/fisiologia , Humanos , Células-Tronco Mesenquimais , Fatores de Crescimento Neural/metabolismo , Crescimento Neuronal/fisiologia , Fosfoproteínas Fosfatases/metabolismo , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Nervo Isquiático/lesões
8.
Elife ; 102021 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-34240706

RESUMO

Voltage-gated sodium channels cluster in macromolecular complexes at nodes of Ranvier to promote rapid nerve impulse conduction in vertebrate nerves. Node assembly in peripheral nerves is thought to be initiated at heminodes at the extremities of myelinating Schwann cells, and fusion of heminodes results in the establishment of nodes. Here we show that assembly of 'early clusters' of nodal proteins in the murine axonal membrane precedes heminode formation. The neurofascin (Nfasc) proteins are essential for node assembly, and the formation of early clusters also requires neuronal Nfasc. Early clusters are mobile and their proteins are dynamically recruited by lateral diffusion. They can undergo fusion not only with each other but also with heminodes, thus contributing to the development of nodes in peripheral axons. The formation of early clusters constitutes the earliest stage in peripheral node assembly and expands the repertoire of strategies that have evolved to establish these essential structures.


Assuntos
Interneurônios/metabolismo , Proteína Nodal/metabolismo , Animais , Axônios/metabolismo , Moléculas de Adesão Celular/metabolismo , Feminino , Gânglios Espinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Condução Nervosa , Sistema Nervoso Periférico , Células de Schwann/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo
9.
J Adv Res ; 31: 1-12, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34194828

RESUMO

Introduction: Intravenous anesthesia with propofol was reported to improve cancer surgical outcomes when compared with inhalational anesthesia. However, the underlying molecular mechanisms largely remain unknown. Objectives: The anti-tumor effects of propofol and the possible underlying mechanism including altered metabolic and signaling pathways were studied in the current study. Methods: The cell viability, proliferation, migration, and invasion of cancer cells were analyzed with CCK-8, Ki-67 staining, wound healing, and Transwell assay, respectively. The protein changes were analyzed with Western blot and immunofluorescent staining. The metabolomics alteration was studied with 1H-NMR spectroscopy. The gene expression regulations were analyzed with PCR gene array and qRT-PCR experiments. Results: In this study, we found that propofol reduced cell viability and inhibited cell proliferation, migration and invasion of lung cancer cells, but not neuroglioma cells. In lung cancer cells, propofol downregulated glucose transporter 1 (GLUT1), mitochondrial pyruvate carrier 1 (MPC1), p-Akt, p-Erk1/2, and hypoxia- inducible factor 1 alpha (HIF-1 α ) expressions and upregulated pigment epithelium-derived factor (PEDF) expression. Propofol increased intracellular glutamate and glycine but decreased acetate and formate whilst increased glucose, lactate, glutamine, succinate, pyruvate, arginine, valine, isoleucine, and leucine and glycerol, and decreased acetate, ethanol, isopropanol in the culture media of lung cancer cells. Furthermore, VEGFA, CTBP1, CST7, CTSK, CXCL12, and CXCR4 gene expressions were downregulated, while NR4A3, RB1, NME1, MTSS1, NME4, SYK, APC, and FAT1 were upregulated following the propofol treatment. Consistent with the phenotypical changes, these molecular and metabolic changes were not found in the neuroglioma cells. Conclusion: Our findings indicated anti-tumor effects of propofol on the lung cancer but not brain cancer, through the regulation of tumor metastasis-related genes, multi-cellular signaling and cellular metabolism.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Propofol/farmacologia , Células A549 , Anestésicos Intravenosos/farmacologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Invasividade Neoplásica/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Serpinas/genética , Serpinas/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Biochemistry (Mosc) ; 86(7): 852-866, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34284712

RESUMO

The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocyte-derived neurotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and functionally different from other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson's disease (PD). That is why CDNF already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance of other neurotransmitter systems, regulation of the processes of neuroplasticity and non-motor behavior. In the present review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.


Assuntos
Fatores de Crescimento Neural/metabolismo , Animais , Apoptose , Estresse do Retículo Endoplasmático , Humanos , Inflamação , Fatores de Crescimento Neural/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Conformação Proteica , Resposta a Proteínas não Dobradas
11.
Mol Med Rep ; 24(4)2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328201

RESUMO

Diabetes­associated neuronal dysfunction (DAND) is one of the serious complications of diabetes, but there is currently no remedy for it. Streptozotocin [2­deoxy­2­(3­methy1­3­nitrosoureido) D­glucopyranose; STZ] is one of the most well­established diabetes inducers and has been used in vivo and in vitro DAND models. The aim of the present study was to demonstrate that C8­B4 microglia transformed by the stimulus of repetitive low­dose lipopolysaccharide (LPSx3­microglia) prevent STZ­induced Neuro­2a neuronal cell death in vitro. The ELISA results showed that neurotrophin­4/5 (NT­4/5) secretion was promoted in LPSx3­microglia and the cell viability assay with trypan blue staining revealed that the culture supernatant of LPSx3­microglia prevented STZ­induced neuronal cell death. In addition, reverse transcription­quantitative PCR showed that neurons treated with the culture supernatant of LPSx3­microglia promoted the gene expression of B­cell lymphoma­extra large and glucose­dependent insulinotropic polypeptide receptor. Furthermore, the inhibition of tyrosine kinase receptor B, a receptor of NT­4/5, suppressed the neuroprotective effect of LPSx3­microglia. Taken together, the present study demonstrated that LPSx3­microglia prevent STZ­induced neuronal death and that NT­4/5 may be involved in the neuroprotective mechanism of LPSx3­microglia.


Assuntos
Morte Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Neurônios/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glicoproteínas de Membrana/antagonistas & inibidores , Camundongos , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores dos Hormônios Gastrointestinais/genética , Estreptozocina/farmacologia , Proteína bcl-X/genética
12.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068002

RESUMO

How millions of axons navigate accurately toward synaptic targets during development is a long-standing question. Over decades, multiple studies have enriched our understanding of axonal pathfinding with discoveries of guidance molecules and morphogens, their receptors, and downstream signalling mechanisms. Interestingly, classification of attractive and repulsive cues can be fluid, as single guidance cues can act as both. Similarly, guidance cues can be secreted, chemotactic cues or anchored, adhesive cues. How a limited set of guidance cues generate the diversity of axonal guidance responses is not completely understood. Differential expression and surface localization of receptors, as well as crosstalk and spatiotemporal patterning of guidance cues, are extensively studied mechanisms that diversify axon guidance pathways. Posttranslational modification is a common, yet understudied mechanism of diversifying protein functions. Many proteins in axonal guidance pathways are glycoproteins and how glycosylation modulates their function to regulate axonal motility and guidance is an emerging field. In this review, we discuss major classes of glycosylation and their functions in axonal pathfinding. The glycosylation of guidance cues and guidance receptors and their functional implications in axonal outgrowth and pathfinding are discussed. New insights into current challenges and future perspectives of glycosylation pathways in neuronal development are discussed.


Assuntos
Axônios/fisiologia , Glicoproteínas/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Glicosilação , Humanos , Transdução de Sinais
13.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069505

RESUMO

Retinoprotective proteins play important roles for retinal tissue integrity. They can directly affect the function and the survival of photoreceptors, and/or indirectly target the retinal pigment epithelium (RPE) and endothelial cells that support these tissues. Retinoprotective proteins are used in basic, translational and in clinical studies to prevent and treat human retinal degenerative disorders. In this review, we provide an overview of proteins that protect the retina and focus on pigment epithelium-derived factor (PEDF), and its effects on photoreceptors, RPE cells, and endothelial cells. We also discuss delivery systems such as pharmacologic and genetic administration of proteins to achieve photoreceptor survival and retinal tissue integrity.


Assuntos
Proteínas do Olho/metabolismo , Fatores de Crescimento Neural/metabolismo , Retina/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Serpinas/metabolismo , Animais , Células Endoteliais/metabolismo , Humanos , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Transporte Proteico/fisiologia , Retina/fisiologia , Degeneração Retiniana/metabolismo , Neurônios Retinianos/metabolismo
14.
Int J Mol Sci ; 22(9)2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-34063170

RESUMO

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.


Assuntos
Mastocitose Sistêmica/etiologia , Animais , Humanos , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Modelos Biológicos , Mutação/genética , Fatores de Crescimento Neural/metabolismo
15.
Biochim Biophys Acta Rev Cancer ; 1876(1): 188580, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34129916

RESUMO

Nerve fibres are distributed throughout the body along with blood and lymphatic vessels. The intrinsic morphological characteristics of nerves and the general characteristics of secretions in the tumour microenvironment provide a solid theoretical basis for exploring how neuronal tissue can influence the progression of laryngeal cancer (LC). The central nervous system (CNS) and the peripheral nervous system (PNS) jointly control many aspects of cancer and have attracted widespread attention in the study of the progression, invasion and metastasis of tumour tissue banks. Stress activates the neuroendocrine response of the human hypothalamus-pituitary-adrenal (HPA) axis. LC cells induce nerve growth in the microenvironment by releasing neurotrophic factors (NTFs), and they can also stimulate neurite formation by secreting axons and axon guides. Conversely, nerve endings secrete factors that attract LC cells; this is known as perineural invasion (PNI) and promotes the progression of the associated cancer. In this paper, we summarize the systematic understanding of the role of neuroregulation in the LC tumour microenvironment (TME) and ways in which the TME accelerates nerve growth, which is closely related to the occurrence of LC.


Assuntos
Orientação de Axônios , Movimento Celular , Sistema Nervoso Central/patologia , Neoplasias Laríngeas/patologia , Sistema Nervoso Periférico/patologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Sistema Nervoso Central/metabolismo , Progressão da Doença , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Neoplasias Laríngeas/metabolismo , Invasividade Neoplásica , Fatores de Crescimento Neural/metabolismo , Células Neuroendócrinas/metabolismo , Células Neuroendócrinas/patologia , Sistema Nervoso Periférico/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Microambiente Tumoral
16.
Invest Ophthalmol Vis Sci ; 62(7): 18, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132748

RESUMO

Purpose: The cornea is richly innervated by the trigeminal ganglion (TG) and its function supported by secretions from the adjacent lacrimal (LG) and meibomian glands (MG). In this study we examined how pigment epithelium-derived factor (PEDF) gene deletion affects the cornea structure and function. Methods: We used PEDF hemizygous and homozygous knockout mice to study effects of PEDF deficiency on corneal innervation assessed by beta tubulin staining, mRNA expression of trophic factors, and PEDF receptors by adjacent supporting glands, corneal sensitivity measured using a Cochet-Bonnet esthesiometer, and tear production using phenol red cotton thread wetting. Results: Loss of PEDF was accompanied by reduced corneal innervation and sensitivity, increased corneal surface injury and tear production, thinning of the corneal stroma and loss of stromal cells. PEDF mRNA was expressed in the cornea and its supporting tissues, the TG, LG, and MG. Deletion of one or both PEDF alleles resulted in decreased expression of essential trophic support in the TG, LG, and MG including nerve growth factor, brain-derived neurotrophic growth factor, and GDNF with significantly increased levels of NT-3 in the LG and decreased EGF expression in the cornea. Decreased transcription of the putative PEDF receptors, adipose triglyceride lipase, lipoprotein receptor-related protein 6, laminin receptor, PLXDC1, and PLXDC2 was also evident in the TG, LG and MG with the first three showing increased levels in corneas of the Pedf+/- and Pedf-/- mice compared to wildtype controls. Constitutive inactivation of ERK1/2 and Akt was pronounced in the TG and cornea, although their protein levels were dramatically increased in Pedf-/- mice. Conclusions: This study highlights an essential role for PEDF in corneal structure and function and confirms the reported rescue of exogenous PEDF treatment in corneal pathologies. The pleiotropic effects of PEDF deletion on multiple trophic factors, receptors and signaling molecules are strong indications that PEDF is a key coordinator of molecular mechanisms that maintain corneal function and could be exploited in therapeutic options for several ocular surface diseases.


Assuntos
Córnea , Doenças da Córnea , Proteínas do Olho , Fatores de Crescimento Neural , Serpinas , Lágrimas/fisiologia , Gânglio Trigeminal , Animais , Córnea/inervação , Córnea/patologia , Córnea/fisiopatologia , Doenças da Córnea/metabolismo , Doenças da Córnea/fisiopatologia , Doenças da Córnea/terapia , Lesões da Córnea/metabolismo , Lesões da Córnea/fisiopatologia , Proteínas do Olho/genética , Proteínas do Olho/farmacologia , Deleção de Genes , Humanos , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/deficiência , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Inibidores de Proteases/farmacologia , Receptores de Neuropeptídeos/metabolismo , Serpinas/deficiência , Serpinas/genética , Serpinas/farmacologia , Gânglio Trigeminal/metabolismo , Gânglio Trigeminal/fisiopatologia , Tubulina (Proteína)/metabolismo , Percepção Visual/fisiologia
17.
Nat Commun ; 12(1): 4005, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183661

RESUMO

Synaptic inputs on cortical dendrites are organized with remarkable subcellular precision at the micron level. This organization emerges during early postnatal development through patterned spontaneous activity and manifests both locally where nearby synapses are significantly correlated, and globally with distance to the soma. We propose a biophysically motivated synaptic plasticity model to dissect the mechanistic origins of this organization during development and elucidate synaptic clustering of different stimulus features in the adult. Our model captures local clustering of orientation in ferret and receptive field overlap in mouse visual cortex based on the receptive field diameter and the cortical magnification of visual space. Including action potential back-propagation explains branch clustering heterogeneity in the ferret and produces a global retinotopy gradient from soma to dendrite in the mouse. Therefore, by combining activity-dependent synaptic competition and species-specific receptive fields, our framework explains different aspects of synaptic organization regarding stimulus features and spatial scales.


Assuntos
Visão Ocular/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Potenciais de Ação/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/fisiologia , Furões , Camundongos , Modelos Neurológicos , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Córtex Visual/anatomia & histologia
18.
Development ; 148(11)2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34109380

RESUMO

The adult nervous system has a limited capacity to regenerate after accidental damage. Post-injury functional restoration requires proper targeting of the injured axon to its postsynaptic cell. Although the initial response to axonal injury has been studied in great detail, it is rather unclear what controls the re-establishment of a functional connection. Using the posterior lateral microtubule neuron in Caenorhabditis elegans, we found that after axotomy, the regrowth from the proximal stump towards the ventral side and accumulation of presynaptic machinery along the ventral nerve cord correlated to the functional recovery. We found that the loss of insulin receptor DAF-2 promoted 'ventral targeting' in a DAF-16-dependent manner. We further showed that coordinated activities of DAF-16 in neuron and muscle promoted 'ventral targeting'. In response to axotomy, expression of the Netrin receptor UNC-40 was upregulated in the injured neuron in a DAF-16-dependent manner. In contrast, the DAF-2-DAF-16 axis contributed to the age-related decline in Netrin expression in muscle. Therefore, our study revealed an important role for insulin signaling in regulating the axon guidance molecules during the functional rewiring process.


Assuntos
Axônios/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Moléculas de Adesão Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Netrinas/metabolismo , Animais , Orientação de Axônios , Proteínas de Caenorhabditis elegans/genética , Moléculas de Adesão Celular/genética , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Microtúbulos/metabolismo , Fatores de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Netrina/metabolismo , Netrinas/genética , Neurônios/metabolismo , Transdução de Sinais
19.
Neuron ; 109(13): 2150-2164.e5, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34038743

RESUMO

Processing of sensory information in neural circuits is modulated by an animal's behavioral state, but the underlying cellular mechanisms are not well understood. Focusing on the mouse visual cortex, here we analyze the role of GABAergic interneurons that are located in layer 1 and express Ndnf (L1 NDNF INs) in the state-dependent control over sensory processing. We find that the ongoing and sensory-evoked activity of L1 NDNF INs is strongly enhanced when an animal is aroused and that L1 NDNF INs gain-modulate local excitatory neurons selectively during high-arousal states by inhibiting their apical dendrites while disinhibiting their somata via Parvalbumin-expressing interneurons. Because active NDNF INs are evenly spread in L1 and can affect excitatory neurons across all cortical layers, this indicates that the state-dependent activation of L1 NDNF INs and the subsequent shift of inhibition in excitatory neurons toward their apical dendrites gain-modulate sensory processing in whole cortical columns.


Assuntos
Comportamento Animal , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Fatores de Crescimento Neural/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Animais , Feminino , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Estimulação Luminosa , Córtex Visual/metabolismo
20.
Otol Neurotol ; 42(8): e1125-e1133, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33973949

RESUMO

HYPOTHESIS: MicroRNAs predicted to regulate neurotrophin signaling can be found in human perilymph. BACKGROUND: Animal and human temporal bone studies suggest that spiral ganglion health can affect cochlear implant (CI) outcomes. Neurotrophins have been identified as a key factor in the maintenance of spiral ganglion health. Changes in miRNAs may regulate neurotrophin signaling and may reflect neurotrophin expression levels. METHODS: Perilymph sampling was carried out in 18 patients undergoing cochlear implantation or stapedotomy. Expression of miRNAs in perilymph was evaluated using an Agilent miRNA gene chip. Using ingenuity pathway analysis (IPA) software, miRNAs targeting neurotrophin signaling pathway genes present in a cochlear cDNA library were annotated. Expression levels of miRNAs in perilymph were correlated to the patients' preoperative pure-tone average. RESULTS: Expression of mRNAs coding for neurotrophins and their receptors were identified in tissue obtained from normal human cochlea during skull base surgery. We identified miRNAs predicted to regulate these signaling cascades, including miR-1207-5p, miR-4651, miR-103-3p, miR-100-5p, miR-221-3p, miR-200-3p. There was a correlation between poor preoperative hearing and lower expression of miR-1207 (predicted to regulate NTR3) and miR-4651 (predicted to regulate NTR2). Additionally, miR-3960, miR-4481, and miR-675 showed significant differences in expression level when comparing mild and profound hearing loss patients. CONCLUSIONS: Expression of some miRNAs that are predicted to regulate neurotrophin signaling in the perilymph of cochlear implant patients vary with the patient's level of residual hearing. These miRNAs may serve as biomarkers for changes in neurotrophin signaling.


Assuntos
Implante Coclear , Implantes Cocleares , MicroRNAs , Fatores de Crescimento Neural/metabolismo , Audição , Humanos , MicroRNAs/genética , Perilinfa/metabolismo , Transdução de Sinais
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