Department of Neurobiology, University of Utah, Salt Lake City, UT, USA.
Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA.
Mol Psychiatry. 2021 Nov;26(11):6868-6879. doi: 10.1038/s41380-021-01135-9. Epub 2021 May 14.
The AKT-mTOR signaling transduction pathway plays an important role in neurodevelopment and synaptic plasticity. mTOR is a serine/threonine kinase that modulates signals from multiple neurotransmitters and phosphorylates specific proteins to regulate protein synthesis and cytoskeletal organization. There is substantial evidence demonstrating abnormalities in AKT expression and activity in different schizophrenia (SZ) models. However, direct evidence for dysregulated mTOR kinase activity and its consequences on downstream effector proteins in SZ pathophysiology is lacking. Recently, we reported reduced phosphorylation of mTOR at an activating site and abnormal mTOR complex formation in the SZ dorsolateral prefrontal cortex (DLPFC). Here, we expand on our hypothesis of disrupted mTOR signaling in the SZ brain and studied the expression and activity of downstream effector proteins of mTOR complexes and the kinase activity profiles of SZ subjects. We found that S6RP phosphorylation, downstream of mTOR complex I, is reduced, whereas PKCα phosphorylation, downstream of mTOR complex II, is increased in SZ DLPFC. In rats chronically treated with haloperidol, we showed that S6RP phosphorylation is increased in the rat frontal cortex, suggesting a potential novel mechanism of action for antipsychotics. We also demonstrated key differences in kinase signaling networks between SZ and comparison subjects for both males and females using kinome peptide arrays. We further investigated the role of mTOR kinase activity by inhibiting it with rapamycin in postmortem tissue and compared the impact of mTOR inhibition in SZ and comparison subjects using kinome arrays. We found that SZ subjects are globally more sensitive to rapamycin treatment and AMP-activated protein kinase (AMPK) contributes to this differential kinase activity. Together, our findings provide new insights into the role of mTOR as a master regulator of kinase activity in SZ and suggest potential targets for therapeutic intervention.
AKT-mTOR 信号转导通路在神经发育和突触可塑性中发挥重要作用。mTOR 是一种丝氨酸/苏氨酸激酶，可调节来自多种神经递质的信号，并磷酸化特定蛋白质以调节蛋白质合成和细胞骨架组织。有大量证据表明，不同精神分裂症（SZ）模型中的 AKT 表达和活性异常。然而，直接证据表明，在 SZ 病理生理学中，mTOR 激酶活性及其对下游效应蛋白的调节异常。最近，我们报道了 SZ 背外侧前额叶皮层（DLPFC）中 mTOR 的一个激活位点磷酸化减少和 mTOR 复合物形成异常。在这里，我们扩展了我们关于 SZ 大脑中 mTOR 信号中断的假设，并研究了 mTOR 复合物下游效应蛋白的表达和活性以及 SZ 受试者的激酶活性谱。我们发现，mTOR 复合物 I 的下游 S6RP 磷酸化减少，而 mTOR 复合物 II 的下游 PKCα 磷酸化增加。在慢性给予氟哌啶醇的大鼠中，我们表明 S6RP 磷酸化在大鼠前额叶皮层中增加，这表明抗精神病药可能具有潜在的新作用机制。我们还使用激酶组肽阵列证明了 SZ 和对照受试者的男性和女性之间的激酶信号网络存在关键差异。我们通过使用 rapamycin 抑制 mTOR 激酶活性进一步研究了 mTOR 激酶活性的作用，并使用激酶组阵列比较了 SZ 和对照受试者中 mTOR 抑制的影响。我们发现 SZ 受试者对 rapamycin 治疗的总体敏感性更高，并且 AMP 激活的蛋白激酶（AMPK）对此差异的激酶活性有贡献。总之，我们的研究结果提供了 mTOR 作为 SZ 中激酶活性的主要调节剂的作用的新见解，并提出了潜在的治疗干预靶点。
