MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease
| العنوان: | MEK1/2 inhibition rescues neurodegeneration by TFEB-mediated activation of autophagic lysosomal function in a model of Alzheimer’s Disease |
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| المؤلفون: | Yoon Sun Chun, Mi-Yeon Kim, Sun-Young Lee, Mi Jeong Kim, Tae-Joon Hong, Jae Kyong Jeon, Dulguun Ganbat, Hyoung Tae Kim, Sang Seong Kim, Tae-In Kam, Sungho Han |
| المصدر: | Molecular Psychiatry. 27:4770-4780 |
| بيانات النشر: | Springer Science and Business Media LLC, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cellular and Molecular Neuroscience, Psychiatry and Mental health, Molecular Biology |
| الوصف: | Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder, which is characterized by cognitive deficit due to synaptic loss and neuronal death. Extracellular amyloid β plaques are one of the pathological hallmarks of AD. The autophagic lysosomal pathway is the essential mechanism to maintain cellular homeostasis by driving clearance of protein aggregates and is dysfunctional in AD. Here, we showed that inhibiting MEK/ERK signaling using a clinically available MEK1/2 inhibitor, trametinib (GSK1120212, SNR1611), induces the protection of neurons through autophagic lysosomal activation mediated by transcription factor EB (TFEB) in a model of AD. Orally administered trametinib recovered impaired neural structures, cognitive functions, and hippocampal long-term potentiation (LTP) in 5XFAD mice. Trametinib also reduced Aβ deposition via induction of autophagic lysosomal activation. RNA-sequencing analysis revealed upregulation of autophagic lysosomal genes by trametinib administration. In addition, trametinib inhibited TFEB phosphorylation at Ser142 and promoted its nuclear translocation, which in turn induced autophagic lysosomal related genes, indicating that trametinib activates the autophagic lysosomal process through TFEB activation. From these observations, we concluded that MEK inhibition provides neuronal protection from the Aβ burden by increasing autophagic lysosomal activity. Thus, MEK inhibition may be an effective therapeutic strategy for AD. |
| تدمد: | 1476-5578 1359-4184 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::1d3d57bd198571b3757be078e9e3ccc4Test https://doi.org/10.1038/s41380-022-01713-5Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....1d3d57bd198571b3757be078e9e3ccc4 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765578 13594184 |
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