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首页> 外文期刊>Neurobiology of disease >Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.
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Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.

机译：Tsc1缺陷前脑的神经元和神经胶质细胞异常，雷帕霉素可部分挽救。

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Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1(Emx1-Cre) conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1(Emx1-Cre) CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.
机译：结节性硬化症（TSC）是一种多器官遗传病，主要特征是脑畸形（块茎），许多患者患有癫痫和自闭症。这些畸形通常表现出神经元和神经胶质细胞异常，并且可能是TSC中所见的许多神经系统疾病的基础。尽管已经一致证明了TSC中mTORC1信号通路的上调，但对于块茎的发病机理仍然知之甚少。在这里，我们通过灭活胚胎神经祖细胞中的小鼠Tsc1基因来解决TSC中异常的大脑发育。这种策略可以评估Tsc1基因在神经元和神经胶质细胞谱系中的作用。 Tsc1（Emx1-Cre）条件性基因敲除（CKO）动物在25天的生命中死亡。他们的大脑增大了大小，并在大脑皮层中包含了显着的大细胞，这些大细胞具有大大增加的mTORC1信号传导和减少的mTORC2信号传导。还发现了严重的皮质叠层缺损，畸形星形胶质细胞增大和髓鞘减少。然后用雷帕霉素处理Tsc1（Emx1-Cre）CKO小鼠，看能否挽救过早死亡和脑部异常。产后雷帕霉素治疗完全预防了过早死亡，并在很大程度上逆转了胶质细胞病变，但未逆转异常的神经元层压。这些发现支持了一个模型，即胚胎神经祖细胞中TSC基因功能的丧失会导致TSC患者的皮质畸形。雷帕霉素的巨大作用表明，即使存在广泛的多谱系异常，TSC患者也可能存在产后治疗窗口。

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