Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model
Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model
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DOI：
10.1093/hmg/ddq563
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发表时间：
2011-03-15
影响因子：
3.5
通讯作者：
Broccoli, Vania
中科院分区：
文献类型：
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作者：
Ricciardi, Sara;Boggio, Elena M.;Broccoli, Vania
Rett 综合征 (RTT) 是一种神经发育障碍，目前尚无有效的治疗方法，大多数情况下是由甲基 CpG 结合蛋白 2 (MECP2) 基因突变引起的。 RTT 在一段明显正常发育的时期后变得明显，并导致生长减慢、严重的精神运动障碍和精神发育迟滞。有效的 RTT 动物模型已经存在，并且显示出突触连接的形态功能异常。然而，MeCP2 破坏导致神经元和突触改变的分子后果尚不清楚。通过哺乳动物雷帕霉素靶点 (mTOR) 途径进行的蛋白质合成调节对于突触组织至关重要，其破坏与许多神经发育疾病有关。我们研究了核糖体蛋白 (rp) S6 的磷酸化，其激活高度依赖于 mTOR 活性。免疫组织化学表明，Mecp2 突变体皮质区域的神经元中 rpS6 磷酸化受到严重影响，并且这种改变发生在疾病的严重症状阶段之前。此外，我们发现症状前 Mecp2 突变体大脑中蛋白质合成起始存在严重缺陷，该缺陷不限于特定的转录物子集。最后，我们提供了与突变大脑疾病进展相关的 Akt/mTOR 普遍功能障碍的证据，但不是细胞外调节激酶的信号传导。我们的结果表明 AKT/mTOR 通路的缺陷导致 Mecp2 突变神经元翻译控制的改变，并揭示了病理过程的一种新的假定生物标志物。重要的是，这项研究提供了治疗干预的新背景，可以设计成功抑制或改善 RTT 的发展。
Rett syndrome (RTT) is a neurodevelopmental disorder with no efficient treatment that is caused in the majority of cases by mutations in the gene methyl-CpG binding-protein 2 (MECP2). RTT becomes manifest after a period of apparently normal development and causes growth deceleration, severe psychomotor impairment and mental retardation. Effective animal models for RTT are available and show morphofunctional abnormalities of synaptic connectivity. However, the molecular consequences of MeCP2 disruption leading to neuronal and synaptic alterations are not known. Protein synthesis regulation via the mammalian target of the rapamycin (mTOR) pathway is crucial for synaptic organization, and its disruption is involved in a number of neurodevelopmental diseases. We investigated the phosphorylation of the ribosomal protein (rp) S6, whose activation is highly dependent from mTOR activity. Immunohistochemistry showed that rpS6 phosphorylation is severely affected in neurons across the cortical areas of Mecp2 mutants and that this alteration precedes the severe symptomatic phase of the disease. Moreover, we found a severe defect of the initiation of protein synthesis in the brain of presymptomatic Mecp2 mutant that was not restricted to a specific subset of transcripts. Finally, we provide evidence for a general dysfunction of the Akt/mTOR, but not extracellular-regulated kinase, signaling associated with the disease progression in mutant brains. Our results indicate that defects in the AKT/mTOR pathway are responsible for the altered translational control in Mecp2 mutant neurons and disclosed a novel putative biomarker of the pathological process. Importantly, this study provides a novel context of therapeutic interventions that can be designed to successfully restrain or ameliorate the development of RTT.