RESUMO
Gaucher disease (GD) is caused by homozygous mutations in the GBA1 gene, which encodes the lysosomal ß-glucosidase (GBA) enzyme. GD affects several organs and tissues, including the brain in certain variants of the disease. Heterozygous GBA1 variants are a major genetic risk factor for developing Parkinson's disease. The RIPK3 kinase is relevant in GD and its deficiency improves the neurological and visceral symptoms in a murine GD model. RIPK3 mediates necroptotic-like cell death: it is unknown whether the role of RIPK3 in GD is the direct induction of necroptosis or if it has a more indirect function by mediating necrosis-independent. Also, the mechanisms that activate RIPK3 in GD are currently unknown. In this study, we show that c-Abl tyrosine kinase participates upstream of RIPK3 in GD. We found that the active, phosphorylated form of c-Abl is increased in several GD models, including patient's fibroblasts and GBA null mice. Furthermore, its pharmacological inhibition with the FDA-approved drug Imatinib decreased RIPK3 signaling. We found that c-Abl interacts with RIPK3, that RIPK3 is phosphorylated at a tyrosine site, and that this phosphorylation is reduced when c-Abl is inhibited. Genetic ablation of c-Abl in neuronal GD and GD mice models significantly reduced RIPK3 activation and MLKL downstream signaling. These results showed that c-Abl signaling is a new upstream pathway that activates RIPK3 and that its inhibition is an attractive therapeutic approach for the treatment of GD.
Assuntos
Apoptose , Doença de Gaucher/patologia , Glucosilceramidase/metabolismo , Neurônios/patologia , Proteínas Proto-Oncogênicas c-abl/fisiologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Glucosilceramidase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necroptose , Neurônios/metabolismo , Fosforilação , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Transdução de SinaisRESUMO
Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.
Assuntos
Doença de Gaucher/metabolismo , Metabolismo dos Lipídeos/genética , Lisossomos/patologia , Doença de Niemann-Pick Tipo A/metabolismo , Doença de Niemann-Pick Tipo C/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Colesterol/metabolismo , Doença de Gaucher/genética , Doença de Gaucher/patologia , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/metabolismo , Mutação , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo A/genética , Doença de Niemann-Pick Tipo A/patologia , Doença de Niemann-Pick Tipo C/genética , Doença de Niemann-Pick Tipo C/patologia , Transdução de Sinais/genética , Esfingolipídeos/metabolismo , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
Alzheimer's disease (AD) is characterized by progressive memory loss and dementia. The strong correlation between cognitive decline and the loss of synapses supports the idea that synaptic damage is a relevant pathogenic mechanism underlying AD progression. It has been shown that amyloid beta oligomers (AßOs) induce synaptotoxicity ultimately leading to the reduction of dendritic spine density, which underlies cognitive damage. However, the signaling pathways connecting AßOs to synaptic dysfunction have not been completely elucidated. In this review, we have gathered evidence on AßOs receptors and the signaling pathways involved in synaptic damage. We make special emphasis on a new AßOs induced axis that involves the tyrosine kinase ephrin receptor A4 (EphA4) and c-Abl tyrosine kinase activation. EphA4 is a key player in homeostatic plasticity, mediating dendritic spine remodeling and retraction. AßOs aberrantly activate EphA4 leading to dendritic spine elimination. c-Abl is activated in AßOs exposed neurons and in AD patient's brain, and the inhibition of activated c-Abl ameliorates cognitive deficits in AD mouse model. The EphA4 receptor activates c-Abl intracellular signaling. Therefore EphA4 is an emerging AßOs receptor and the activation of the EphA4/c-Abl axis would explain the synaptic spine alterations found in AD.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Receptor EphA4/metabolismo , Transdução de Sinais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Espinhas Dendríticas/genética , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Humanos , Camundongos , Proteínas Proto-Oncogênicas c-abl/genética , Receptor EphA4/genética , Sinapses/genética , Sinapses/metabolismo , Sinapses/patologiaRESUMO
BACKGROUND: Niemann-Pick type C (NPC) disease is characterized by lysosomal accumulation of cholesterol. Interestingly, NPC patients' brains also show increased levels of amyloid-ß (Aß) peptide, a key protein in Alzheimer's disease pathogenesis. We previously reported that the c-Abl tyrosine kinase is active in NPC neurons and in AD animal models and that Imatinib, a specific c-Abl inhibitor, decreased the amyloid burden in brains of the AD mouse model. Active c-Abl was shown to interact with the APP cytosolic domain, but the relevance of this interaction to APP processing has yet to be defined. RESULTS: In this work we show that c-Abl inhibition reduces APP amyloidogenic cleavage in NPC cells overexpressing APP. Indeed, we found that levels of the Aß oligomers and the carboxy-terminal fragment ßCTF were decreased when the cells were treated with Imatinib and upon shRNA-mediated c-Abl knockdown. Moreover, Imatinib decreased APP amyloidogenic processing in the brain of an NPC mouse model. In addition, we found decreased levels of ßCTF in neuronal cultures from c-Abl null mice. We demonstrate that c-Abl directly interacts with APP, that c-Abl inhibition prevents this interaction, and that Tyr682 in the APP cytoplasmic tail is essential for this interaction. More importantly, we found that c-Abl inhibition by Imatinib significantly inhibits the interaction between APP and BACE1. CONCLUSION: We conclude that c-Abl activity facilitates the APP-BACE1 interaction, thereby promoting amyloidogenic processing of APP. Thus, inhibition of c-Abl could be a pharmacological target for preventing the injurious effects of increased Aß levels in NPC disease.
RESUMO
Hyperphosphorylated tau is a cardinal feature of Alzheimer's disease (AD) pathology. The deregulation of kinases that phosphorylate tau can alter normal tau-related processes, including microtubule dynamics, growth cones, and axonal transport, and induce tau aggregation in paired helical filaments. Here we discuss the possible roles of the Abl family of tyrosine kinases, which are essential regulators of cytoskeleton cellular signaling cascades, in AD tau pathology and how the physiological roles of Abl kinases could be connected with the cytoskeletal alterations induced by Aß aggregates and AD progression.
Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Emaranhados Neurofibrilares/metabolismo , Proteínas Proto-Oncogênicas c-abl/metabolismo , Transdução de Sinais/fisiologia , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Encéfalo/patologia , Humanos , Emaranhados Neurofibrilares/patologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, amyloid-ß peptide (Aß) accumulation and synaptic alterations. Previous studies indicated that hyperforin, a component of the St John's Wort, prevents Aß neurotoxicity and some behavioral impairments in a rat model of AD. In this study we examined the ability of tetrahydrohyperforin (IDN5607), a stable hyperforin derivative, to prevent the cognitive deficit and synaptic impairment in an in vivo model of AD. In double transgenic APPswe/PSEN1ΔE9 mice, IDN5706 improves memory and prevents the impairment of synaptic plasticity in a dose-dependent manner, inducing a recovery of long-term potentiation. In agreement with these findings, IDN5706 prevented the decrease in synaptic proteins in hippocampus and cortex. In addition, decreased levels of tau hyperphosphorylation, astrogliosis, and total fibrillar and oligomeric forms of Aß were determined in double transgenic mice treated with IDN5706. In cultured cells, IDN5706 decreased the proteolytic processing of the amyloid precursor protein that leads to Aß peptide generation. These findings indicate that IDN5706 ameliorates AD neuropathology and could be considered of therapeutic relevance in AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Floroglucinol/análogos & derivados , Presenilina-1/genética , Processamento de Proteína Pós-Traducional , Transmissão Sináptica/genética , Terpenos/farmacologia , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/antagonistas & inibidores , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Floroglucinol/administração & dosagem , Floroglucinol/farmacologia , Processamento de Proteína Pós-Traducional/genética , Transmissão Sináptica/efeitos dos fármacos , Terpenos/administração & dosagemRESUMO
The aim of the present study was to evaluate clinical and laboratory features of acute severe asthma (ASA) in children and their outcome of mechanical ventilation (MV). Twenty ASA episodes admitted to the hospital with hypercapnia (HC) and/or lost of consciousness (LC) and/or severe non reversible bronchial obstruction (NRBO) were retrospectively studied. Long lasting asthma and frequent admissions were registered in the majority of cases. In HC group (14 cases) the PaCO2 was 70 +/- 26 mmHg (X +/- SD). Hypercapnia was associated with intravenous administration of sodium bicarbonate in three cases. In NRBO group (4 cases) the acute response to salbutamol brought out during the first week of treatment and it was associated with increased basal forced expiratory volume in one second (FEV1). Ten cases were treated with MV because of hypercapnia and/or lost of consciousness, seizures (one case), and cardiac arrest (one case). The later patient died in 24 hours. Pneumothorax and atelectasis (one case), and pneumonia (one case) were the complications of mechanical ventilation. Three cases with PaO2 less than 60 mmHg and four cases with FEV1 less than 60% were sent home. After 27 days one patient from the later group had a new episode of ASA. Arterial gases and expiratory flow measurements are paramount tools for close monitoring of children with ASA. It is suggested that normalization of those parameters are an essential criteria for discharging those patients.
Assuntos
Asma/fisiopatologia , Estado Asmático/fisiopatologia , Adolescente , Monitorização Transcutânea dos Gases Sanguíneos , Broncospirometria , Criança , Pré-Escolar , Doença Crônica , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Respiração Artificial , Estudos RetrospectivosRESUMO
The condition of first permanent molars in a cohort of children born in Cuba, during the week comprised from March the 1st. to 7, 1973, is presented now when they are 11 years old. Maxillary teeth presented a better conservation level than mandibular teeth. Non valuable differences were found in the condition of teeth of one or another hemiarch. It was found that 80.9% of the children had one or more molars affected by caries.
Assuntos
Cárie Dentária/epidemiologia , Dente Molar/patologia , Criança , Estudos de Coortes , Cuba/epidemiologia , Humanos , Dente Impactado/epidemiologiaRESUMO
Se analiza retrospectivamente 25 casos de melanoma cutáneo tratado por los autores en un período de 10 años. Los pacientes se catalogan según criterio de Clark-Breslow y se establece correlación entre evolución y mayor mortalidad en el grupo de alto riesgo. La técnica de tratamiento incluyó cirugía resectiva amplia y uso de procedimientos como injerto y colgajo. La sobrevida fue de 60% (15 casos) con un seguimiento de 54 meses. El seguimiento de la serie fue de 100%. El compromiso ganglionar que se presentó en los pacientes de esta serie determinó un pronóstico sombrío
Assuntos
Humanos , Masculino , Feminino , Neoplasias Cutâneas/cirurgia , Melanoma , Retalhos CirúrgicosAssuntos
Infecções Bacterianas/diagnóstico , Infecções por Haemophilus , Derrame Pleural/diagnóstico , Infecções Pneumocócicas , Antígenos de Bactérias/análise , Bactérias/isolamento & purificação , Criança , Pré-Escolar , Contraimunoeletroforese , Haemophilus influenzae , Humanos , Lactente , Derrame Pleural/etiologia , Derrame Pleural/imunologia , Derrame Pleural/microbiologiaRESUMO
After both splenectomized and non-splenectomized mice had received a total amount of five doses of Busulfan at a rate of 0.14 mg/48 h, the recovery of their erythropoietic organs through the addition of 59Fe was investigated, after the cytostatic treatment had been cut off. In the non-splenectomized animals recovery was clear, keeping high 59Fe uptake values, significantly above normal, throughout the 21 days of the experiment. In the splenectomized mice, 59Fe uptake reached a peak of 38 per cent three days after the supply had been cut off, and from then on it descended to subnormal values.