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1.
Proc Natl Acad Sci U S A ; 114(23): E4676-E4685, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28533375

RESUMO

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.


Assuntos
Doença de Huntington/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Adulto , Idoso , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Doença de Huntington/genética , Proteína 1 Associada a ECH Semelhante a Kelch/química , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/química , Células-Tronco Neurais/metabolismo , Fármacos Neuroprotetores/farmacologia , Conformação Proteica/efeitos dos fármacos , Ratos , Transdução de Sinais
2.
Alcohol ; 107: 56-72, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36038084

RESUMO

Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 50 million people worldwide. Early life risk factors for AD, including prenatal exposures, remain underexplored. Exposure of the fetus to alcohol (ethanol) is not uncommon during pregnancy, and may result in physical, behavioral, and cognitive changes that are first detected during childhood but result in lifelong challenges. Whether or not prenatal ethanol exposure may contribute to Alzheimer's disease risk is not yet known. Here we exposed a mouse model of Alzheimer's disease (3xTg-AD), bearing three dementia-associated transgenes, presenilin1 (PS1M146V), human amyloid precursor protein (APPSwe), and human tau (TauP301S), to ethanol on gestational days 13.5-16.5 using an established binge-type maternal ethanol exposure paradigm. We sought to investigate whether prenatal ethanol exposure resulted in a precocious onset or increased severity of AD progression, or both. We found that a brief binge-type gestational exposure to ethanol during a period of peak neuronal migration to the developing cortex resulted in an earlier onset of spatial memory deficits and behavioral inflexibility in the progeny, as assessed by performance on the modified Barnes maze task. The observed cognitive changes coincided with alterations to both GABAergic and glutamatergic synaptic transmission in layer V/VI neurons, diminished GABAergic interneurons, and increased ß-amyloid accumulation in the medial prefrontal cortex. These findings provide the first preclinical evidence for prenatal ethanol exposure as a potential factor for modifying the onset of AD-like behavioral dysfunction and set the groundwork for more comprehensive investigations into the underpinnings of AD-like cognitive changes in individuals with fetal alcohol spectrum disorders.


Assuntos
Doença de Alzheimer , Cognição , Etanol , Neurônios , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Camundongos , Gravidez , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Etanol/toxicidade , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/genética
3.
Sci Rep ; 8(1): 11355, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-30054496

RESUMO

The Hippo signaling pathway is involved in organ size regulation and tumor suppression. Although inhibition of Hippo leads to tumorigenesis, activation of Hippo may play a role in neurodegeneration. Specifically, activation of the upstream regulator, mammalian sterile 20 (STE20)-like kinase 1 (MST1), reduces activity of the transcriptional co-activator Yes-Associated Protein (YAP), thereby mediating oxidative stress-induced neuronal death. Here, we investigated the possible role of this pathway in Huntington's disease (HD) pathogenesis. Our results demonstrate a significant increase in phosphorylated MST1, the active form, in post-mortem HD cortex and in the brains of CAG knock-in HdhQ111/Q111 mice. YAP nuclear localization was also decreased in HD post-mortem cortex and in neuronal stem cells derived from HD patients. Moreover, there was a significant increase in phosphorylated YAP, the inactive form, in HD post-mortem cortex and in HdhQ111/Q111 brain. In addition, YAP was found to interact with huntingtin (Htt) and the chaperone 14-3-3, however this interaction was not altered in the presence of mutant Htt. Lastly, YAP/TEAD interactions and expression of Hippo pathway genes were altered in HD. Together, these results demonstrate that activation of MST1 together with a decrease in nuclear YAP could significantly contribute to transcriptional dysregulation in HD.


Assuntos
Encéfalo/patologia , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Células-Tronco Neurais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Proteínas 14-3-3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Modelos Animais de Doenças , Via de Sinalização Hippo , Humanos , Células-Tronco Neurais/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição , Transcrição Gênica , Proteínas de Sinalização YAP
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