The mechanistic target of rapamycin (mTOR) is a kinase at the center of an evolutionarily conserved signaling pathway that orchestrates cell growth and metabolism. mTOR responds to an array of intra- and extracellular stimuli and in turn controls multiple cellular anabolic and catabolic processes. Aberrant mTOR activity is associated with numerous diseases, with particularly profound impact on the nervous system. mTOR is found in two protein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), which are governed by different upstream regulators and have distinct cellular actions. Mutations in genes encoding for mTOR regulators result in a collection of neurodevelopmental disorders known as mTORopathies. While these disorders can affect multiple organs, neuropsychiatric conditions such as epilepsy, intellectual disability, and autism spectrum disorder have a major impact on quality of life. The neuropsychiatric aspects of mTORopathies have been particularly challenging to treat in a clinical setting. Current therapeutic approaches center on rapamycin and its analogs, drugs that are administered systemically to inhibit mTOR activity. While these drugs show some clinical efficacy, adverse side effects, incomplete suppression of mTOR targets, and lack of specificity for mTORC1 or mTORC2 may limit their utility. An increased understanding of the neurobiology of mTOR and the underlying molecular, cellular, and circuit mechanisms of mTOR-related disorders will facilitate the development of improved therapeutics. Animal models of mTORopathies have helped unravel the consequences of mTOR pathway mutations in specific brain cell types and developmental stages, revealing an array of disease-related phenotypes. In this review, we discuss current progress and potential future directions for the therapeutic treatment of mTORopathies with a focus on findings from genetic mouse models.
Dev Neurosci

中文翻译：

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mTORopathies 治疗的当前方法和未来方向

雷帕霉素 (mTOR) 的机制靶标是一种激酶，位于进化上保守的信号通路的中心，协调细胞生长和代谢。mTOR 对一系列细胞内和细胞外刺激做出反应，进而控制多个细胞合成代谢和分解代谢过程。mTOR 活性异常与多种疾病相关，尤其对神经系统的影响尤为深远。mTOR 存在于两种蛋白质复合物中：mTOR 复合物 1 (mTORC1) 和 2 (mTORC2)，它们由不同的上游调节因子控制并具有不同的细胞作用。mTOR 调节因子编码基因突变会导致一系列神经发育障碍，称为 mTORopathies。虽然这些疾病可以影响多个器官，但癫痫、智力障碍和自闭症谱系障碍等神经精神疾病对生活质量有重大影响。mTORopathies 的神经精神方面在临床环境中治疗起来特别具有挑战性。目前的治疗方法集中在雷帕霉素及其类似物，这些药物是全身给药以抑制 mTOR 活性的。虽然这些药物显示出一些临床疗效，但不良副作用、mTOR 靶标的不完全抑制以及 mTORC1 或 mTORC2 缺乏特异性可能会限制它们的实用性。加深对 mTOR 神经生物学以及 mTOR 相关疾病的分子、细胞和回路机制的了解将有助于改进治疗方法的开发。mTORopathies 动物模型帮助揭示了 mTOR 通路突变对特定脑细胞类型和发育阶段的影响，揭示了一系列与疾病相关的表型。在这篇综述中，我们讨论了 mTORopathies 治疗的当前进展和潜在的未来方向，重点关注遗传小鼠模型的发现。
开发神经科学