Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Mais filtros











Base de dados
Intervalo de ano de publicação
1.
Brain ; 144(10): 3226-3238, 2021 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-33964142

RESUMO

Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders. Using a biochemical assay for SARM1 NADase we identified a novel series of potent and selective irreversible isothiazole inhibitors of SARM1 enzymatic activity that protected rodent and human axons in vitro. In sciatic nerve axotomy, we observed that these irreversible SARM1 inhibitors decreased a rise in nerve cADPR and plasma neurofilament light chain released from injured sciatic nerves in vivo. In a mouse paclitaxel model of CIPN we determined that Sarm1 knockout mice prevented loss of axonal function, assessed by sensory nerve action potential amplitudes of the tail nerve, in a gene-dosage-dependent manner. In that CIPN model, the irreversible SARM1 inhibitors prevented loss of intraepidermal nerve fibres induced by paclitaxel and provided partial protection of axonal function assessed by sensory nerve action potential amplitude and mechanical allodynia.


Assuntos
Proteínas do Domínio Armadillo/antagonistas & inibidores , Axônios/efeitos dos fármacos , Proteínas do Citoesqueleto/antagonistas & inibidores , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Tiazóis/uso terapêutico , Animais , Antineoplásicos Fitogênicos/toxicidade , Proteínas do Domínio Armadillo/deficiência , Proteínas do Domínio Armadillo/genética , Axônios/metabolismo , Células Cultivadas , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Knockout , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/metabolismo , Tiazóis/farmacologia
2.
Protein Cell ; 12(8): 621-638, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33871822

RESUMO

Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, non-human primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.


Assuntos
Proteínas do Domínio Armadillo/genética , Colite Ulcerativa/genética , Proteínas do Citoesqueleto/genética , Sistema Nervoso Entérico/metabolismo , Doenças Neurodegenerativas/genética , Animais , Proteínas do Domínio Armadillo/deficiência , Catecolaminas/metabolismo , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/diagnóstico por imagem , Colite Ulcerativa/metabolismo , Colo/diagnóstico por imagem , Colo/metabolismo , Colo/patologia , Proteínas do Citoesqueleto/deficiência , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Sistema Nervoso Entérico/diagnóstico por imagem , Sistema Nervoso Entérico/patologia , Regulação da Expressão Gênica , Humanos , Imageamento Tridimensional , Interleucina-17/genética , Interleucina-17/metabolismo , Macaca mulatta , Masculino , Camundongos , Camundongos Knockout , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Norepinefrina/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
3.
Commun Biol ; 3(1): 49, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001778

RESUMO

Protecting the nervous system from chronic effects of physical and chemical stress is a pressing clinical challenge. The obligate pro-degenerative protein Sarm1 is essential for Wallerian axon degeneration. Thus, blocking Sarm1 function is emerging as a promising neuroprotective strategy with therapeutic relevance. Yet, the conditions that will most benefit from inhibiting Sarm1 remain undefined. Here we combine genome engineering, pharmacology and high-resolution intravital videmicroscopy in zebrafish to show that genetic elimination of Sarm1 increases Schwann-cell resistance to toxicity by diverse chemotherapeutic agents after axonal injury. Synthetic degradation of Sarm1-deficient axons reversed this effect, suggesting that glioprotection is a non-autonomous effect of delayed axon degeneration. Moreover, loss of Sarm1 does not affect macrophage recruitment to nerve-wound microenvironment, injury resolution, or neural-circuit repair. These findings anticipate that interventions aimed at inhibiting Sarm1 can counter heightened glial vulnerability to chemical stressors and may be an effective strategy to reduce chronic consequences of neurotrauma.


Assuntos
Antineoplásicos/efeitos adversos , Proteínas do Domínio Armadillo/deficiência , Axônios/metabolismo , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Degeneração Walleriana/genética , Animais , Animais Geneticamente Modificados , Proteínas do Domínio Armadillo/genética , Axônios/patologia , Imunofluorescência , Loci Gênicos , Mutagênese , Fenótipo , Peixe-Zebra
4.
Cell Death Dis ; 9(11): 1116, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389906

RESUMO

Apoptotic cells expose Phosphatidylserine (PS), that serves as an "eat me" signal for engulfing cells. Previous studies have shown that PS also marks degenerating axonsduring developmental pruning or in response to insults (Wallerian degeneration), but the pathways that control PS exposure on degenerating axons are largely unknown. Here, we used a series of in vitro assays to systematically explore the regulation of PS exposure during axonal degeneration. Our results show that PS exposure is regulated by the upstream activators of axonal pruning and Wallerian degeneration. However, our investigation of signaling further downstream revealed divergence between axon degeneration and PS exposure. Importantly, elevation of the axonal energetic status hindered PS exposure, while inhibition of mitochondrial activity caused PS exposure, without degeneration. Overall, our results suggest that the levels of PS on the outer axonal membrane can be dissociated from the degeneration process and that the axonal energetic status plays a key role in the regulation of PS exposure.


Assuntos
Gânglios Espinais/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Fosfatidilserinas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Degeneração Walleriana/metabolismo , Trifosfato de Adenosina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas do Domínio Armadillo/deficiência , Proteínas do Domínio Armadillo/genética , Axotomia , Biomarcadores/metabolismo , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Embrião de Mamíferos , Gânglios Espinais/metabolismo , Gânglios Espinais/patologia , Expressão Gênica , Camundongos , Camundongos Knockout , Técnicas Analíticas Microfluídicas , Fator de Crescimento Neural/farmacologia , Plasticidade Neuronal/genética , Fosfatidilserinas/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Técnicas de Cultura de Tecidos , Vincristina/farmacologia , Degeneração Walleriana/genética , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/genética
5.
J Peripher Nerv Syst ; 22(3): 162-171, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28485482

RESUMO

Distal axon degeneration seen in many peripheral neuropathies is likely to share common molecular mechanisms with Wallerian degeneration. Although several studies in mouse models of peripheral neuropathy showed prevention of axon degeneration in the slow Wallerian degeneration (Wlds) mouse, the role of a recently identified player in Wallerian degeneration, Sarm1, has not been explored extensively. In this study, we show that mice lacking the Sarm1 gene are resistant to distal axonal degeneration in a model of chemotherapy induced peripheral neuropathy caused by paclitaxel and a model of high fat diet induced putative metabolic neuropathy. This study extends the role of Sarm1 to axon degeneration seen in peripheral neuropathies and identifies it as a likely target for therapeutic development.


Assuntos
Proteínas do Domínio Armadillo/deficiência , Proteínas do Citoesqueleto/deficiência , Dieta Hiperlipídica/efeitos adversos , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/prevenção & controle , Potenciais de Ação/genética , Análise de Variância , Animais , Antineoplásicos Fitogênicos/toxicidade , Proteínas do Domínio Armadillo/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Hiperalgesia/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Condução Nervosa/genética , Paclitaxel/toxicidade , Limiar da Dor/fisiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Tempo de Reação/genética , Nervo Sural/patologia
6.
Development ; 138(10): 2099-109, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21521738

RESUMO

Defects in the development or maintenance of tubule diameter correlate with polycystic kidney disease. Here, we report that absence of the cadherin regulator p120 catenin (p120ctn) from the renal mesenchyme prior to tubule formation leads to decreased cadherin levels with abnormal morphologies of early tubule structures and developing glomeruli. In addition, mutant mice develop cystic kidney disease, with markedly increased tubule diameter and cellular proliferation, and detached luminal cells only in proximal tubules. The p120ctn homolog Arvcf is specifically absent from embryonic proximal tubules, consistent with the specificity of the proximal tubular phenotype. p120ctn knockdown in renal epithelial cells in 3D culture results in a similar cystic phenotype with reduced levels of E-cadherin and active RhoA. We find that E-cadherin knockdown, but not RhoA inhibition, phenocopies p120ctn knockdown. Taken together, our data show that p120ctn is required for early tubule and glomerular morphogenesis, as well as control of luminal diameter, probably through regulation of cadherins.


Assuntos
Cateninas/metabolismo , Glomérulos Renais/embriologia , Glomérulos Renais/metabolismo , Túbulos Renais/embriologia , Túbulos Renais/metabolismo , Animais , Proteínas do Domínio Armadillo/deficiência , Proteínas do Domínio Armadillo/genética , Proteínas do Domínio Armadillo/metabolismo , Sequência de Bases , Caderinas/deficiência , Caderinas/genética , Caderinas/metabolismo , Cateninas/deficiência , Cateninas/genética , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Polaridade Celular , Proliferação de Células , Citoesqueleto/metabolismo , Cães , Feminino , Técnicas de Silenciamento de Genes , Doenças Renais Císticas/embriologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Modelos Biológicos , Morfogênese , Néfrons/embriologia , Néfrons/metabolismo , Fenótipo , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Gravidez , RNA Interferente Pequeno/genética , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP , delta Catenina
7.
J Virol ; 83(18): 9329-38, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19587044

RESUMO

Sterile alpha and HEAT/Armadillo motif (SARM) is a highly conserved Toll/interleukin-1 receptor (TIR)-containing adaptor protein that is believed to negatively regulate signaling of the pathogen recognition receptors Toll-like receptor 3 (TLR3) and TLR4. To test its physiological function in the context of a microbial infection, we generated SARM(-/-) mice and evaluated the impact of this deficiency on the pathogenesis of West Nile virus (WNV), a neurotropic flavivirus that requires TLR signaling to restrict infection. Although SARM was preferentially expressed in cells of the central nervous system (CNS), studies with primary macrophages, neurons, or astrocytes showed no difference in viral growth kinetics. In contrast, viral replication was increased specifically in the brainstem of SARM(-/-) mice, and this was associated with enhanced mortality after inoculation with a virulent WNV strain. A deficiency of SARM was also linked to reduced levels of tumor necrosis factor alpha (TNF-alpha), decreased microglia activation, and increased neuronal death in the brainstem after WNV infection. Thus, SARM appears to be unique among the TIR adaptor molecules, since it functions to restrict viral infection and neuronal injury in a brain region-specific manner, possibly by modulating the activation of resident CNS inflammatory cells.


Assuntos
Proteínas do Domínio Armadillo/fisiologia , Tronco Encefálico/patologia , Proteínas do Citoesqueleto/fisiologia , Microglia/fisiologia , Fator de Necrose Tumoral alfa/biossíntese , Vírus do Nilo Ocidental/patogenicidade , Animais , Proteínas do Domínio Armadillo/análise , Proteínas do Domínio Armadillo/deficiência , Tronco Encefálico/virologia , Morte Celular , Proteínas do Citoesqueleto/análise , Proteínas do Citoesqueleto/deficiência , Camundongos , Camundongos Knockout , Neurônios/patologia , Neurônios/virologia , Distribuição Tecidual , Receptores Toll-Like
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA