Saré Rachel Michelle, Torossian Anita, Loutaev Inna, Smith Carolyn Beebe
Department of Health and Human Services, Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20814.
Department of Health and Human Services, Section on Neuroadaptation and Protein Metabolism, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20814
eNeuro. 2022 Jul 18;9(4). doi: 10.1523/ENEURO.0480-21.2022.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that results in intellectual disability and, in ∼50% of patients, autism spectrum disorder. The protein products that are altered in TSC (TSC1 and TSC2) form a complex to inhibit the mammalian target of rapamycin [mTOR; mTOR complex 1 (mTORC1)] pathway. This pathway has been shown to affect the process of mRNA translation through its action on ribosomal protein S6 and 4-elongation binding protein 1. It is thought that mutations in the TSC proteins lead to upregulation of the mTORC1 pathway and consequently an increase in protein synthesis. Unexpectedly, our previous study of a mouse model of TSC ( ) demonstrated decreased rates of protein synthesis throughout the brain. In the present study, we confirm those results in another +/- mouse model, one with a different mutation locus and on a mixed background ( +/-). We also examine mTORC1 signaling and possible effects of prior isoflurane anesthesia. Because measurements of protein synthesis rates require surgical preparation of the animal and anesthesia, we examine mTORC1 signaling pathways both under baseline conditions and following recovery from anesthesia. Our results demonstrate regionally selective effects of prior anesthesia. Overall, our results in both models suggest differences to the central hypothesis regarding TSC and show the importance of studying protein synthesis Protein synthesis is an important process for brain function. In the disorder, tuberous sclerosis complex (TSC), the inhibition of the mammalian target of rapamycin (mTOR) pathway is reduced and this is thought to lead to excessive protein synthesis. Most studies of protein synthesis in models of TSC have been conducted We report here confirmation of our previous study showing decreased brain protein synthesis rates in a second mouse model of TSC, results counter to the central hypothesis regarding TSC. We also explore the possible influence of prior isoflurane exposure on signaling pathways involved in regulation of protein synthesis. This study highlights a novel aspect of TSC and the importance of studying cellular processes .
结节性硬化症（TSC）是一种常染色体显性疾病，可导致智力残疾，约50%的患者还患有自闭症谱系障碍。TSC中发生改变的蛋白质产物（TSC1和TSC2）形成一种复合物，以抑制雷帕霉素哺乳动物靶标[mTOR；mTOR复合物1（mTORC1）]信号通路。该信号通路已被证明通过其对核糖体蛋白S6和4-延伸结合蛋白1的作用来影响mRNA翻译过程。据认为，TSC蛋白中的突变会导致mTORC1信号通路上调，从而导致蛋白质合成增加。出乎意料的是，我们之前对TSC小鼠模型的研究表明，整个大脑中的蛋白质合成速率降低。在本研究中，我们在另一种+/-小鼠模型中证实了这些结果，该模型具有不同的突变位点且背景混合（+/-）。我们还研究了mTORC1信号传导以及先前异氟烷麻醉的可能影响。由于蛋白质合成速率的测量需要对动物进行手术准备和麻醉，我们在基线条件下以及麻醉恢复后都研究了mTORC1信号通路。我们的结果表明先前麻醉具有区域选择性作用。总体而言，我们在两种模型中的结果表明与关于TSC的核心假设存在差异，并表明研究蛋白质合成的重要性。蛋白质合成是大脑功能的重要过程。在结节性硬化症（TSC）这种疾病中，雷帕霉素哺乳动物靶标（mTOR）信号通路的抑制作用减弱，这被认为会导致蛋白质合成过多。大多数关于TSC模型中蛋白质合成的研究都是在……进行的。我们在此报告，证实了我们之前的研究，即在第二个TSC小鼠模型中大脑蛋白质合成速率降低，这一结果与关于TSC的核心假设相反。我们还探讨了先前异氟烷暴露对参与蛋白质合成调节的信号通路的可能影响。这项研究突出了TSC的一个新方面以及研究细胞过程的重要性。
