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1.
Cell ; 185(1): 62-76, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34963057

RESUMO

Brain-derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions daunting. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Transtornos Mentais/metabolismo , Plasticidade Neuronal/fisiologia , Neuropeptídeos/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Homeostase/fisiologia , Humanos , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/genética , Neurogênese/fisiologia , Neuropeptídeos/genética , Psicotrópicos/farmacologia , Psicotrópicos/uso terapêutico , Transmissão Sináptica/efeitos dos fármacos , Resultado do Tratamento
2.
Cell ; 167(1): 47-59.e15, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27616062

RESUMO

Thermoregulation is one of the most vital functions of the brain, but how temperature information is converted into homeostatic responses remains unknown. Here, we use an unbiased approach for activity-dependent RNA sequencing to identify warm-sensitive neurons (WSNs) within the preoptic hypothalamus that orchestrate the homeostatic response to heat. We show that these WSNs are molecularly defined by co-expression of the neuropeptides BDNF and PACAP. Optical recordings in awake, behaving mice reveal that these neurons are selectively activated by environmental warmth. Optogenetic excitation of WSNs triggers rapid hypothermia, mediated by reciprocal changes in heat production and loss, as well as dramatic cold-seeking behavior. Projection-specific manipulations demonstrate that these distinct effectors are controlled by anatomically segregated pathways. These findings reveal a molecularly defined cell type that coordinates the diverse behavioral and autonomic responses to heat. Identification of these warm-sensitive cells provides genetic access to the core neural circuit regulating the body temperature of mammals. PAPERCLIP.


Assuntos
Regulação da Temperatura Corporal/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Regulação da Expressão Gênica , Temperatura Alta , Neurônios/fisiologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Núcleo Hipotalâmico Ventromedial/citologia , Animais , Comportamento Animal , Camundongos , Microdissecção , Neurônios/metabolismo , Optogenética , RNA Mensageiro/genética , Proteína S6 Ribossômica/metabolismo , Análise de Sequência de RNA , Núcleo Hipotalâmico Ventromedial/metabolismo
3.
Cell ; 167(1): 233-247.e17, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27662091

RESUMO

Mammalian DNA methylation is a critical epigenetic mechanism orchestrating gene expression networks in many biological processes. However, investigation of the functions of specific methylation events remains challenging. Here, we demonstrate that fusion of Tet1 or Dnmt3a with a catalytically inactive Cas9 (dCas9) enables targeted DNA methylation editing. Targeting of the dCas9-Tet1 or -Dnmt3a fusion protein to methylated or unmethylated promoter sequences caused activation or silencing, respectively, of an endogenous reporter. Targeted demethylation of the BDNF promoter IV or the MyoD distal enhancer by dCas9-Tet1 induced BDNF expression in post-mitotic neurons or activated MyoD facilitating reprogramming of fibroblasts into myoblasts, respectively. Targeted de novo methylation of a CTCF loop anchor site by dCas9-Dnmt3a blocked CTCF binding and interfered with DNA looping, causing altered gene expression in the neighboring loop. Finally, we show that these tools can edit DNA methylation in mice, demonstrating their wide utility for functional studies of epigenetic regulation.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Edição de Genes/métodos , Proteínas Proto-Oncogênicas/metabolismo , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fator de Ligação a CCCTC , Proteína 9 Associada à CRISPR , Linhagem Celular , Ilhas de CpG , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Endonucleases/metabolismo , Elementos Facilitadores Genéticos , Genoma , Camundongos , Proteína MyoD/metabolismo , Neurônios/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo
4.
J Biol Chem ; 300(6): 107411, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38796067

RESUMO

The myocyte enhancer factor (MEF2) family of transcription factors, originally discovered for its pivotal role in muscle development and function, has emerged as an essential regulator in various aspects of brain development and neuronal plasticity. The MEF2 transcription factors are known to regulate numerous important genes in the nervous system, including brain-derived neurotrophic factor (BDNF), a small secreted neurotrophin responsible for promoting the survival, growth, and differentiation of neurons. The expression of the Bdnf gene is spatiotemporally controlled by various transcription factors binding to both its proximal and distal regulatory regions. While previous studies have investigated the connection between MEF2 transcription factors and Bdnf, the endogenous function of MEF2 factors in the transcriptional regulation of Bdnf remains largely unknown. Here, we aimed to deepen the knowledge of MEF2 transcription factors and their role in the regulation of Bdnf comparatively in rat cortical and hippocampal neurons. As a result, we demonstrate that the MEF2 transcription factor-dependent enhancer located at -4.8 kb from the Bdnf gene regulates the endogenous expression of Bdnf in hippocampal neurons. In addition, we confirm neuronal activity-dependent activation of the -4.8 kb enhancer in vivo. Finally, we show that specific MEF2 family transcription factors have unique roles in the regulation of Bdnf, with the specific function varying based on the particular brain region and stimuli. Altogether, we present MEF2 family transcription factors as crucial regulators of Bdnf expression, fine-tuning Bdnf expression through both distal and proximal regulatory regions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Elementos Facilitadores Genéticos , Hipocampo , Fatores de Transcrição MEF2 , Neurônios , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fatores de Transcrição MEF2/metabolismo , Fatores de Transcrição MEF2/genética , Animais , Hipocampo/metabolismo , Hipocampo/citologia , Neurônios/metabolismo , Neurônios/citologia , Ratos , Córtex Cerebral/metabolismo , Córtex Cerebral/citologia , Regulação da Expressão Gênica , Células Cultivadas , Ratos Sprague-Dawley
5.
Genes Cells ; 29(1): 99-105, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38009531

RESUMO

Suppressor of cancer cell invasion (SCAI) acts as a transcriptional repressor of serum response factor (SRF)-mediated gene expression by binding to megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF), which is an SRF transcriptional coactivator. Growing evidence suggests that SCAI is a negative regulator of neuronal morphology, whereas MKL2/MRTFB is a positive regulator. The mRNA expression of SCAI is downregulated during brain development, suggesting that a reduction in SCAI contributes to the reduced suppression of SRF-mediated gene induction, thus increasing dendritic complexity and developing neuronal circuits. In the present study, we hypothesized that brain-derived neurotrophic factor (BDNF), which is important for neuronal plasticity and development, might alter SCAI mRNA levels. We therefore investigated the effects of BDNF on SCAI mRNA levels in primary cultured cortical neurons. Furthermore, because alternative splicing generates several SCAI variants in the brain, we measured SCAI variant mRNA after BDNF stimulation. Both SCAI variant 1 and total SCAI mRNA expression levels were downregulated by BDNF. Moreover, the extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) pathway was involved in the BDNF-mediated decrease in SCAI mRNA expression. Our findings provide insights into the molecular mechanism underlying a neurotrophic factor switch for the repressive transcriptional complex that includes SCAI.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neurônios , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neurônios/metabolismo , Regulação da Expressão Gênica , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Invasividade Neoplásica , Células Cultivadas
6.
FASEB J ; 38(2): e23411, 2024 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-38243766

RESUMO

Autism spectrum disorder is discussed in the context of altered neural oscillations and imbalanced cortical excitation-inhibition of cortical origin. We studied here whether developmental changes in peripheral auditory processing, while preserving basic hearing function, lead to altered cortical oscillations. Local field potentials (LFPs) were recorded from auditory, visual, and prefrontal cortices and the hippocampus of BdnfPax2 KO mice. These mice develop an autism-like behavioral phenotype through deletion of BDNF in Pax2+ interneuron precursors, affecting lower brainstem functions, but not frontal brain regions directly. Evoked LFP responses to behaviorally relevant auditory stimuli were weaker in the auditory cortex of BdnfPax2 KOs, connected to maturation deficits of high-spontaneous rate auditory nerve fibers. This was correlated with enhanced spontaneous and induced LFP power, excitation-inhibition imbalance, and dendritic spine immaturity, mirroring autistic phenotypes. Thus, impairments in peripheral high-spontaneous rate fibers alter spike synchrony and subsequently cortical processing relevant for normal communication and behavior.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Audição , Fenótipo
7.
Mol Psychiatry ; 29(7): 1990-2000, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38351172

RESUMO

Methamphetamine use disorder (MUD) is characterized by loss of control over compulsive drug use. Here, we used a self-administration (SA) model to investigate transcriptional changes associated with the development of early and late compulsivity during contingent footshocks. Punishment initially separated methamphetamine taking rats into always shock-resistant (ASR) rats that continued active lever pressing and shock-sensitive (SS) rats that reduced their lever pressing. At the end of the punishment phase, rats underwent 15 days of forced abstinence at the end of which they were re-introduced to the SA paradigm followed by SA plus contingent shocks. Interestingly, 36 percent of the initial SS rats developed delayed shock-resistance (DSR). Of translational relevance, ASR rats showed more incubation of methamphetamine craving than DSR and always sensitive (AS) rats. RNA sequencing revealed increased striatal Rab37 and Dipk2b mRNA levels that correlated with incubation of methamphetamine craving. Interestingly, Bdnf mRNA levels showed HDAC2-dependent decreased expression in the AS rats. The present SA paradigm should help to elucidate the molecular substrates of early and late addiction-like behaviors.


Assuntos
Corpo Estriado , Fissura , Redes Reguladoras de Genes , Metanfetamina , Punição , Autoadministração , Animais , Metanfetamina/farmacologia , Ratos , Fissura/fisiologia , Masculino , Corpo Estriado/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Ratos Sprague-Dawley , Comportamento de Procura de Droga/fisiologia , Comportamento Aditivo/genética , Comportamento Aditivo/metabolismo , Modelos Animais de Doenças
8.
Mol Psychiatry ; 29(3): 660-670, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38228888

RESUMO

Obesity and anxiety are morbidities notable for their increased impact on society during the recent COVID-19 pandemic. Understanding the mechanisms governing susceptibility to these conditions will increase our quality of life and resilience to future pandemics. In the current study, we explored the function of a highly conserved regulatory region (BE5.1) within the BDNF gene that harbours a polymorphism strongly associated with obesity (rs10767664; p = 4.69 × 10-26). Analysis in primary cells suggested that the major T-allele of BE5.1 was an enhancer, whereas the obesity-associated A-allele was not. However, CRISPR/CAS9 deletion of BE5.1 from the mouse genome (BE5.1KO) produced no significant effect on the expression of BDNF transcripts in the hypothalamus, no change in weight gain after 28 days and only a marginally significant increase in food intake. Nevertheless, transcripts were significantly increased in the amygdala of female mice and elevated zero maze and marble-burying tests demonstrated a significant increase in anxiety-like behaviour that could be reversed by diazepam. Consistent with these observations, human GWAS cohort analysis demonstrated a significant association between rs10767664 and anxiousness in human populations. Intriguingly, interrogation of the human GTEx eQTL database demonstrated no effect on BDNF mRNA levels associated with rs10767664 but a highly significant effect on BDNF-antisense (BDNF-AS) gene expression and splicing. The subsequent observation that deletion of BE5.1 also significantly reduced BDNF-AS expression in mice suggests a novel mechanism in the regulation of BDNF expression common to mice and humans, which contributes to the modulation of mood and anxiety in both species.


Assuntos
Ansiedade , Fator Neurotrófico Derivado do Encéfalo , Obesidade , Polimorfismo de Nucleotídeo Único , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ansiedade/genética , Ansiedade/metabolismo , Humanos , Camundongos , Obesidade/genética , Obesidade/metabolismo , Feminino , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico/genética , Camundongos Endogâmicos C57BL , COVID-19 , Alelos , Hipotálamo/metabolismo , Estudo de Associação Genômica Ampla/métodos , Comportamento Animal/fisiologia , Tonsila do Cerebelo/metabolismo , Predisposição Genética para Doença/genética
9.
Cell ; 142(1): 52-64, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20603014

RESUMO

Cancer is influenced by its microenvironment, yet broader, environmental effects also play a role but remain poorly defined. We report here that mice living in an enriched housing environment show reduced tumor growth and increased remission. We found this effect in melanoma and colon cancer models, and that it was not caused by physical activity alone. Serum from animals held in an enriched environment (EE) inhibited cancer proliferation in vitro and was markedly lower in leptin. Hypothalamic brain-derived neurotrophic factor (BDNF) was selectively upregulated by EE, and its genetic overexpression reduced tumor burden, whereas BDNF knockdown blocked the effect of EE. Mechanistically, we show that hypothalamic BDNF downregulated leptin production in adipocytes via sympathoneural beta-adrenergic signaling. These results suggest that genetic or environmental activation of this BDNF/leptin axis may have therapeutic significance for cancer.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neoplasias do Colo/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Melanoma/metabolismo , Transdução de Sinais , Meio Social , Adipócitos/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Neoplasias do Colo/genética , Neoplasias do Colo/fisiopatologia , Genes APC , Abrigo para Animais , Hipotálamo/citologia , Imunocompetência , Melanoma/genética , Melanoma/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Processos Neoplásicos , Distribuição Aleatória , Receptores Adrenérgicos beta/metabolismo
10.
Mol Ther ; 32(5): 1407-1424, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429927

RESUMO

Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small-fiber innervation and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new therapies are needed for treatment of this condition affecting 20-30 million Americans. Here, we validated a gene therapy approach using an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors (brain-derived neurotrophic factor [BDNF] and nerve growth factor [NGF]) directly to scWAT to improve tissue-specific PN as a proof-of-concept approach. AAVRec2-BDNF intra-adipose delivery improved tissue innervation in obese/diabetic mice with PN, but after longer periods of dietary obesity there was reduced efficacy, revealing a key time window for therapies. AAVRec2-NGF also increased scWAT innervation in obese mice and was more effective than BDNF, likely because Rec2 targeted adipocytes, the tissue's endogenous NGF source. AAVRec2-NGF also worked well even after 25 weeks of dietary obesity, unlike BDNF, which likely needs a vector that targets its physiological cellular source (stromal vascular fraction cells). Given the differing effects of AAVs carrying NGF versus BDNF, a combined therapy may be ideal for PN.


Assuntos
Adipócitos , Fator Neurotrófico Derivado do Encéfalo , Dependovirus , Terapia Genética , Vetores Genéticos , Obesidade , Gordura Subcutânea , Animais , Dependovirus/genética , Obesidade/terapia , Obesidade/metabolismo , Camundongos , Terapia Genética/métodos , Adipócitos/metabolismo , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Gordura Subcutânea/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/genética , Técnicas de Transferência de Genes , Humanos , Masculino , Doenças do Sistema Nervoso Periférico/terapia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/genética , Transdução Genética
11.
Mol Ther ; 32(7): 2113-2129, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38788710

RESUMO

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Disfunção Cognitiva , Proteínas do Citoesqueleto , Modelos Animais de Doenças , Hipocampo , Plasticidade Neuronal , Encefalopatia Associada a Sepse , Animais , Camundongos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/terapia , Disfunção Cognitiva/genética , Encefalopatia Associada a Sepse/metabolismo , Encefalopatia Associada a Sepse/etiologia , Encefalopatia Associada a Sepse/terapia , Encefalopatia Associada a Sepse/genética , Hipocampo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Dependovirus/genética , Masculino , Potenciação de Longa Duração , Receptor trkB/metabolismo , Receptor trkB/genética , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Sinapses/metabolismo
12.
Proc Natl Acad Sci U S A ; 119(32): e2201151119, 2022 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-35930664

RESUMO

Epilepsy is a devastating brain disorder for which effective treatments are very limited. There is growing interest in early intervention, which requires a better mechanistic understanding of the early stages of this disorder. While diverse brain insults can lead to epileptic activity, a common cellular mechanism relies on uncontrolled recurrent excitatory activity. In the dentate gyrus, excitatory mossy cells (MCs) project extensively onto granule cells (GCs) throughout the hippocampus, thus establishing a recurrent MC-GC-MC excitatory loop. MCs are implicated in temporal lobe epilepsy, a common form of epilepsy, but their role during initial seizures (i.e., before the characteristic MC loss that occurs in late stages) is unclear. Here, we show that initial seizures acutely induced with an intraperitoneal kainic acid (KA) injection in adult mice, a well-established model that leads to experimental epilepsy, not only increased MC and GC activity in vivo but also triggered a brain-derived neurotrophic factor (BDNF)-dependent long-term potentiation (LTP) at MC-GC excitatory synapses. Moreover, in vivo induction of MC-GC LTP using MC-selective optogenetic stimulation worsened KA-induced seizures. Conversely, Bdnf genetic removal from GCs, which abolishes LTP, and selective MC silencing were both anticonvulsant. Thus, initial seizures are associated with MC-GC synaptic strengthening, which may promote later epileptic activity. Our findings reveal a potential mechanism of epileptogenesis that may help in developing therapeutic strategies for early intervention.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Epilepsia , Potenciação de Longa Duração , Fibras Musgosas Hipocampais , Convulsões , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Epilepsia/fisiopatologia , Ácido Caínico/farmacologia , Camundongos , Fibras Musgosas Hipocampais/efeitos dos fármacos , Fibras Musgosas Hipocampais/fisiopatologia , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
13.
Am J Physiol Cell Physiol ; 326(6): C1735-C1752, 2024 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-38618701

RESUMO

The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Propofol , Receptor alfa de Ácido Retinoico , Propofol/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Apoptose/efeitos dos fármacos , Masculino
14.
J Cell Mol Med ; 28(11): e18365, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38818577

RESUMO

Traditional Chinese medicine, particularly Zhi-zi-chi decoction (ZZCD), is gaining recognition as a potential treatment for depression. This study aimed to uncover the molecular mechanisms behind ZZCD's antidepressant effects, focusing on lncRNA Six3os1 and histone H3K4 methylation at the BDNF promoter. Network pharmacology and in vivo experiments were conducted to identify ZZCD targets and evaluate its impact on depression-related behaviours and neuron injury. The role of Six3os1 in recruiting KMT2A to the BDNF promoter and its effects on oxidative stress and neuron injury were investigated. ZZCD reduced depression-like behaviours and neuron injury in mice subjected to chronic stress. It upregulated Six3os1, which facilitated KMT2A recruitment to the BDNF promoter, leading to increased histone H3K4 methylation and enhanced BDNF expression. ZZCD also inhibited CORT-induced neuron injury, inflammatory response and oxidative stress in vitro. ZZCD's antidepressant properties involve Six3os1 upregulation, which exerts neuroprotective effects by inhibiting oxidative stress and neuron injury, thereby alleviating depressive symptoms. Targeting Six3os1 upregulation may offer a potential therapeutic intervention for depression.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Depressão , Medicamentos de Ervas Chinesas , Histonas , Regiões Promotoras Genéticas , RNA Longo não Codificante , Animais , Masculino , Camundongos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/tratamento farmacológico , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Metilação/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
15.
J Biol Chem ; 299(2): 102897, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36639028

RESUMO

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival and growth during development. In the adult nervous system, BDNF is important for synaptic function in several biological processes such as memory formation and food intake. In addition, BDNF has been implicated in development and maintenance of the cardiovascular system. The Bdnf gene comprises several alternative untranslated 5' exons and two variants of 3' UTRs. The effects of these entire alternative UTRs on translatability have not been established. Using reporter and translating ribosome affinity purification analyses, we show that prevalent Bdnf 5' UTRs, but not 3' UTRs, exert a repressive effect on translation. However, contrary to previous reports, we do not detect a significant effect of neuronal activity on BDNF translation. In vivo analysis via knock-in conditional replacement of Bdnf 3' UTR by bovine growth hormone 3' UTR reveals that Bdnf 3' UTR is required for efficient Bdnf mRNA and BDNF protein production in the brain, but acts in an inhibitory manner in lung and heart. Finally, we show that Bdnf mRNA is enriched in rat brain synaptoneurosomes, with higher enrichment detected for exon I-containing transcripts. In conclusion, these results uncover two novel aspects in understanding the function of Bdnf UTRs. First, the long Bdnf 3' UTR does not repress BDNF expression in the brain. Second, exon I-derived 5' UTR has a distinct role in subcellular targeting of Bdnf mRNA.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , RNA Mensageiro , Regiões não Traduzidas , Animais , Bovinos , Ratos , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Éxons , Neurônios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regiões não Traduzidas/fisiologia
16.
J Biol Chem ; 299(9): 105102, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37507021

RESUMO

The Vps10p domain receptor SorCS2 is crucial for the development and function of the nervous system and essential for brain-derived neurotrophic factor (BDNF)-induced changes in neuronal morphology and plasticity. SorCS2 regulates the subcellular trafficking of the BDNF signaling receptor TrkB as well as selected neurotransmitter receptors in a manner that is dependent on the SorCS2 intracellular domain (ICD). However, the cellular machinery and adaptor protein (AP) interactions that regulate receptor trafficking via the SorCS2 ICD are unknown. We here identify four splice variants of human SorCS2 differing in the insertion of an acidic cluster motif and/or a serine residue within the ICD. We show that each variant undergoes posttranslational proteolytic processing into a one- or two-chain receptor, giving rise to eight protein isoforms, the expression of which differs between neuronal and nonneuronal tissues and is affected by cellular stressors. We found that the only variants without the serine were able to rescue BDNF-induced branching of SorCS2 knockout hippocampal neurons, while variants without the acidic cluster showed increased interactions with clathrin-associated APs AP-1, AP-2, and AP-3. Using yeast two-hybrid screens, we further discovered that all variants bound dynein light chain Tctex-type 3; however, only variants with an acidic cluster motif bound kinesin light chain 1. Accordingly, splice variants showed markedly different trafficking properties and localized to different subcellular compartments. Taken together, our findings demonstrate the existence of eight functional SorCS2 isoforms with differential capacity for interactions with cytosolic ligands dynein light chain Tctex-type 3 and kinesin light chain 1, which potentially allows cell-type specific SorCS2 trafficking and BDNF signaling.


Assuntos
Processamento Alternativo , Sistema Nervoso Central , Receptores de Superfície Celular , Humanos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Processamento Alternativo/fisiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dineínas/metabolismo , Cinesinas/metabolismo , Ligação Proteica , Isoformas de Proteínas/metabolismo , Receptor trkB/metabolismo , Receptores de Superfície Celular/metabolismo , Sistema Nervoso Central/crescimento & desenvolvimento , Processamento de Proteína Pós-Traducional , Transporte Proteico/genética
17.
Glia ; 72(1): 90-110, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37632136

RESUMO

Brain-derived neurotrophic factor (BDNF) plays a fundamental role in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. Dysregulation of BDNF synthesis, secretion or signaling has been associated with many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Although the transcriptional regulation of the Bdnf gene has been extensively studied in neurons, less is known about the regulation and function of BDNF in non-neuronal cells. The most abundant type of non-neuronal cells in the brain, astrocytes, express BDNF in response to catecholamines. However, genetic elements responsible for this regulation have not been identified. Here, we investigated four potential Bdnf enhancer regions and based on reporter gene assays, CRISPR/Cas9 engineering and CAPTURE-3C-sequencing we conclude that a region 840 kb upstream of the Bdnf gene regulates catecholamine-dependent expression of Bdnf in rodent astrocytes. We also provide evidence that this regulation is mediated by CREB and AP1 family transcription factors. This is the first report of an enhancer coordinating the transcription of Bdnf gene in non-neuronal cells.


Assuntos
Astrócitos , Fator Neurotrófico Derivado do Encéfalo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Astrócitos/metabolismo , Catecolaminas/metabolismo , Fatores de Transcrição/metabolismo , Neurônios/metabolismo , Roedores/metabolismo
18.
Stroke ; 55(8): 2094-2102, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38979623

RESUMO

BACKGROUND: Genetic association studies can reveal biology and treatment targets but have received limited attention for stroke recovery. STRONG (Stroke, Stress, Rehabilitation, and Genetics) was a prospective, longitudinal (1-year), genetic study in adults with stroke at 28 US stroke centers. The primary aim was to examine the association that candidate genetic variants have with (1) motor/functional outcomes and (2) stress-related outcomes. METHODS: For motor/functional end points, 3 candidate gene variants (ApoE ε4, BDNF [brain-derived neurotrophic factor], and a dopamine polygenic score) were analyzed for associations with change in grip strength (3 months-baseline), function (3-month Stroke Impact Scale-Activities of Daily Living), mood (3-month Patient Health Questionnaire-8), and cognition (12-month telephone-Montreal Cognitive Assessment). For stress-related outcomes, 7 variants (serotonin transporter gene-linked promoter region, ACE [angiotensin-converting enzyme], oxytocin receptor, FKBP5 [FKBP prolyl isomerase 5], FAAH [fatty acid amide hydrolase], BDNF, and COMT [catechol-O-methyltransferase]) were assessed for associations with posttraumatic stress disorder ([PTSD]; PTSD Primary Care Scale) and depression (Patient Health Questionnaire-8) at 6 and 12 months; stress-related genes were examined as a function of poststroke stress level. Statistical models (linear, negative binomial, or Poisson regression) were based on response variable distribution; all included stroke severity, age, sex, and ancestry as covariates. Stroke subtype was explored secondarily. Data were Holm-Bonferroni corrected. A secondary replication analysis tested whether the rs1842681 polymorphism (identified in the GISCOME study [Genetics of Ischaemic Stroke Functional Outcome]) was related to 3-month modified Rankin Scale score in STRONG. RESULTS: The 763 enrollees were 63.1±14.9 (mean±SD) years of age, with a median initial National Institutes of Health Stroke Scale score of 4 (interquartile range, 2-9); outcome data were available in n=515 at 3 months, n=500 at 6 months, and n=489 at 12 months. At 1 year poststroke, the rs6265 (BDNF) variant was associated with poorer cognition (0.9-point lower telephone-Montreal Cognitive Assessment score, P=1×10-5). For stress-related outcomes, rs4291 (ACE) and rs324420 (FAAH) were risk factors linking increased poststroke stress with higher 1-year depression and PTSD symptoms (P<0.05), while rs4680 (COMT) linked poststroke stress with lower 1-year depression and PTSD. Findings were unchanged when considering stroke subtype. STRONG replicated GISCOME: rs1842681 was associated with lower 3-month modified Rankin Scale score (P=3.2×10-5). CONCLUSIONS: This study identified genetic associations with cognitive function, depression, and PTSD 1 year poststroke. Genetic susceptibility to PTSD and depressive symptoms varied according to the amount of poststroke stress, underscoring the critical role of lived experiences in recovery. Together, the results suggest that genetic association studies provide insights into the biology of stroke recovery in humans.


Assuntos
Recuperação de Função Fisiológica , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Acidente Vascular Cerebral/genética , Recuperação de Função Fisiológica/genética , Estudos Prospectivos , Variação Genética/genética , Reabilitação do Acidente Vascular Cerebral , Estudos Longitudinais , Fator Neurotrófico Derivado do Encéfalo/genética , Estresse Psicológico/genética , Catecol O-Metiltransferase/genética
19.
Neurobiol Dis ; 195: 106501, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38583640

RESUMO

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.


Assuntos
Transporte Axonal , Fator Neurotrófico Derivado do Encéfalo , Doença de Charcot-Marie-Tooth , Modelos Animais de Doenças , Animais , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Camundongos , Tirosina-tRNA Ligase/genética , Tirosina-tRNA Ligase/metabolismo , Humanos , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Receptor trkB/metabolismo , Receptor trkB/genética , Mutação
20.
Prostate ; 84(11): 1016-1024, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38804836

RESUMO

BACKGROUND: Our research focused on the assessment of the impact of systemic inhibition of Trk receptors, which bind to nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), on bladder hypersensitivity in two distinct rodent models of prostatic inflammation (PI). METHODS: Male Sprague-Dawley rats were divided into three groups (n = 6 each): the control group (no PI, vehicle administration), the untreated group (PI, vehicle administration), and the treated group (PI, nonselective Trk inhibitor, GNF 5837, administration). PI in rats was induced by a intraprostatic injection of 5% formalin. Posttreatment, we carried out conscious cystometry and a range of histological and molecular analyses. Moreover, the study additionally evaluated the effects of a nonselective Trk inhibitor on bladder overactivity in a mouse model of PI, which was induced by prostate epithelium-specific conditional deletion of E-cadherin. RESULTS: The rat model of PI showed upregulations of NGF and BDNF in both bladder and prostate tissues in association with bladder overactivity and inflammation in the ventral lobes of the prostate. GNF 5837 treatment effectively mitigated these PI-induced changes, along with reductions in TrkA, TrkB, TrkC, and TRPV1 mRNA expressions in L6-S1 dorsal root ganglia. Also, in the mouse PI model, GNF 5837 treatment similarly improved bladder overactivity. CONCLUSIONS: The findings of our study suggest that Trk receptor inhibition, which reduced bladder hypersensitivity and inflammatory responses in the prostate, along with a decrease in overexpression of Trk and TRPV1 receptors in sensory pathways, could be an effective treatment strategy for male lower urinary tract symptoms associated with PI and bladder overactivity.


Assuntos
Prostatite , Receptor trkA , Bexiga Urinária Hiperativa , Animais , Masculino , Camundongos , Ratos , Administração Oral , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fator de Crescimento Neural/antagonistas & inibidores , Fator de Crescimento Neural/genética , Fator de Crescimento Neural/metabolismo , Próstata/efeitos dos fármacos , Próstata/patologia , Próstata/metabolismo , Prostatite/tratamento farmacológico , Prostatite/patologia , Prostatite/metabolismo , Ratos Sprague-Dawley , Receptor trkA/antagonistas & inibidores , Receptor trkA/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/patologia , Bexiga Urinária/metabolismo , Bexiga Urinária Hiperativa/tratamento farmacológico , Bexiga Urinária Hiperativa/etiologia
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