Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency
Therapeutic inhibition of mTORC2 rescues the behavioral and neurophysiological abnormalities associated with Pten-deficiency
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DOI：
10.1038/s41591-019-0608-y
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发表时间：
2019-11-01
期刊：
影响因子：
82.9
通讯作者：
Costa-Mattioli, Mauro
中科院分区：
文献类型：
--
作者：
Chen, Chien-Ju;Sgritta, Martina;Costa-Mattioli, Mauro
哺乳动物雷帕霉素靶标(MTOR)信号的调节失调，由两个结构和功能不同的复合体mTORC1和mTORC2介导，已被认为与几种神经疾病有关(1-3)。携带磷酸酶和紧张素同源基因(PTEN)基因功能丧失突变的个体，是mTOR信号的负向调节因子，容易患上巨头症、自闭症谱系障碍(ASD)、癫痫发作和智力残疾(2，4，5)。通常认为，与PTEN缺失和其他mORopy相关的神经系统症状(例如，结节性硬化症基因TSC1或TSC2的突变)是由于mTORC1介导的蛋白质合成(1，2，4，6，7)的过度激活所致。利用分子遗传学，我们出人意料地发现，mTORC2(但不是mTORC1)活性的基因缺失延长了小鼠的寿命，抑制了癫痫发作，挽救了ASD样行为和长期记忆，并使缺乏Pten的小鼠大脑的代谢变化正常化。在一种更具治疗性的方法中，我们发现针对mTORC2‘S定义成分Rictor的反义寡核苷酸的注射特异性地抑制了mTORC2的活性，并逆转了青春期Pten缺陷小鼠的行为和神经生理异常。总之，我们的发现表明，mTORC2是与Pten缺乏相关的神经病理生理学的主要驱动因素，它的治疗减少可能代表着一种有前途的、广泛有效的翻译疗法，用于mTOR信号失控的神经疾病。
Dysregulation of the mammalian target of rapamycin (mTOR) signaling, which is mediated by two structurally and functionally distinct complexes, mTORC1 and mTORC2, has been implicated in several neurological disorders(1-3). Individuals carrying loss-of-function mutations in the phosphatase and tensin homolog (PTEN) gene, a negative regulator of mTOR signaling, are prone to developing macrocephaly, autism spectrum disorder (ASD), seizures and intellectual disability(2,4,5). It is generally believed that the neurological symptoms associated with loss of PTEN and other mTORopathies (for example, mutations in the tuberous sclerosis genes TSC1 or TSC2) are due to hyperactivation of mTORC1-mediated protein synthesis(1,2,4,6,7). Using molecular genetics, we unexpectedly found that genetic deletion of mTORC2 (but not mTORC1) activity prolonged lifespan, suppressed seizures, rescued ASD-like behaviors and long- term memory, and normalized metabolic changes in the brain of mice lacking Pten. In a more therapeutically oriented approach, we found that administration of an antisense oligonucleotide (ASO) targeting mTORC2's defining component Rictor specifically inhibits mTORC2 activity and reverses the behavioral and neurophysiological abnormalities in adolescent Pten-deficient mice. Collectively, our findings indicate that mTORC2 is the major driver underlying the neuropathophysiology associated with Pten-deficiency, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where mTOR signaling is dysregulated.