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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Imbalanced Mechanistic Target of Rapamycin C1 and C2 Activity in the Cerebellum of Angelman Syndrome Mice Impairs Motor Function
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Imbalanced Mechanistic Target of Rapamycin C1 and C2 Activity in the Cerebellum of Angelman Syndrome Mice Impairs Motor Function

机译：Angelman综合征小鼠小脑中雷帕霉素C1和C2活性的不平衡机制靶标损害运动功能

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Angelman syndrome (AS) is a neurogenetic disorder caused by deficiency of maternally expressed ubiquitin-protein ligase E3A (UBE3A), an E3 ligase that targets specific proteins for proteasomal degradation. Although motor function impairment occurs in all patients with AS, very little research has been done to understand and treat it. The present study focuses on Ube3A deficiency-induced alterations in signaling through the mechanistic target of rapamycin (mTOR) pathway in the cerebellum of the AS mouse model and on potential therapeutic applications of rapamycin. Levels of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR, were increased in AS mice compared with wild-type mice; however, TSC2 inhibitory phosphorylation was also increased. Correspondingly, levels of phosphorylated/active mTOR were increased. Phosphorylation of the mTORC1 substrates S6 kinase 1 (S6K1) and S6 was elevated, whereas that of the mTORC2 substrates AKT and N-myc downstream regulated 1 was decreased, suggesting enhanced mTORC1 but inhibited mTORC2 signaling. Semi-chronic treatment of AS mice with rapamycin not only improved their motor performance but also normalized mTORC1 and mTORC2 signaling. Furthermore, inhibitory phosphorylation of rictor, a key regulatory/structural subunit of the mTORC2 complex, was increased in AS mice and decreased after rapamycin treatment. These results indicate that Ube3A deficiency leads to overactivation of the mTORC1-S6K1 pathway, which in turn inhibits rictor, resulting in decreased mTORC2 signaling in Purkinje neurons of AS mice. Finally, rapamycin treatment also improved dendritic spine morphology in AS mice, through inhibiting mTORC1 and possibly enhancing mTORC2-mediated regulation of synaptic cytoskeletal elements. Collectively, our results indicate that the imbalance between mTORC1 and mTORC2 activity may contribute to synaptic pathology and motor impairment in AS.
机译：Angelman综合征（AS）是一种由母体表达的泛素蛋白连接酶E3A（UBE3A）缺乏引起的神经遗传疾病，UB3A是一种针对蛋白酶体降解的特定蛋白的E3连接酶。尽管运动功能障碍发生在所有AS患者中，但很少进行研究来了解和治疗它。本研究的重点是在AS小鼠模型小脑中通过雷帕霉素（mTOR）途径的机械靶点通过Ube3A缺乏引起的信号转导以及雷帕霉素的潜在治疗应用。与野生型小鼠相比，AS小鼠的结节性硬化复合物2（TSC2）（mTOR的负调节剂）的水平升高;然而，TSC2抑制性磷酸化也增加了。相应地，磷酸化/活性mTOR的水平增加。 mTORC1底物S6激酶1（S6K1）和S6的磷酸化增强，而mTORC2底物AKT和N-myc下游调节的1的磷酸化降低，表明mTORC1增强，但抑制了mTORC2信号传导。雷帕霉素对AS小鼠的半慢性治疗不仅改善了它们的运动能力，而且使mTORC1和mTORC2信号转导正常化。此外，rictor（mTORC2复合物的关键调节/结构亚基）的抑制性磷酸化在AS小鼠中增加，在雷帕霉素治疗后降低。这些结果表明，Ube3A缺乏会导致mTORC1-S6K1通路过度激活，进而抑制蓖麻毒素，导致AS小鼠Purkinje神经元中的mTORC2信号传导减少。最后，雷帕霉素治疗还通过抑制mTORC1并可能增强mTORC2介导的突触细胞骨架成分的调节，改善了AS小鼠的树突棘形态。总的来说，我们的结果表明mTORC1和mTORC2活性之间的失衡可能有助于AS的突触病理和运动障碍。

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