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Proc Natl Acad Sci U S A ; 120(28): e2302143120, 2023 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-37399380

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease affecting motor neurons and characterized by microglia-mediated neurotoxic inflammation whose underlying mechanisms remain incompletely understood. In this work, we reveal that MAPK/MAK/MRK overlapping kinase (MOK), with an unknown physiological substrate, displays an immune function by controlling inflammatory and type-I interferon (IFN) responses in microglia which are detrimental to primary motor neurons. Moreover, we uncover the epigenetic reader bromodomain-containing protein 4 (Brd4) as an effector protein regulated by MOK, by promoting Ser492-phospho-Brd4 levels. We further demonstrate that MOK regulates Brd4 functions by supporting its binding to cytokine gene promoters, therefore enabling innate immune responses. Remarkably, we show that MOK levels are increased in the ALS spinal cord, particularly in microglial cells, and that administration of a chemical MOK inhibitor to ALS model mice can modulate Ser492-phospho-Brd4 levels, suppress microglial activation, and modify the disease course, indicating a pathophysiological role of MOK kinase in ALS and neuroinflammation.


Assuntos
Esclerose Lateral Amiotrófica , Proteínas que Contêm Bromodomínio , Proteínas Quinases Ativadas por Mitógeno , Doenças Neurodegenerativas , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Modelos Animais de Doenças , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas que Contêm Bromodomínio/genética , Proteínas que Contêm Bromodomínio/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo
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