Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex
Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex
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DOI：
10.1097/wco.0b013e32834451c4
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Sahin, Mustafa
中科院分区：
文献类型：
--
作者：
Tsai, Peter;Sahin, Mustafa
综述目的影响认知的孟德尔疾病提供了一个独特的机会，通过检查动物的遗传缺陷和发展可以在人类身上进行测试的假设来研究神经发育障碍的机制。结节性硬化症 (TSC) 是一种遗传性疾病，表现为癫痫、自闭症和智力障碍。在这里，我们回顾了对 TSC 发病机制和可通过调节来治疗神经系统症状的信号通路的理解的最新进展。最近的研究结果表明，越来越多的证据表明 TSC 患者存在有助于神经表型发展的非结节异常，特别是轴突束的紊乱和髓鞘形成缺陷。 TSC 小鼠模型未能完全复制人类神经病理学，但揭示了细胞异常和神经行为表型。最重要的是，细胞培养和动物模型已将 mTORC1 通路确定为该疾病的治疗靶点。总结临床前数据强烈表明 TSC 是一种神经元连接异常的疾病。神经发育缺陷的高发生率、在很小的时候就可以早期发现该疾病以及 mTORC1 抑制剂的可用性使得 TSC 成为其他孟德尔神经认知障碍的模型，以及基于机制的神经发育障碍治疗试验的途径。
Purpose of reviewMendelian disorders that affect cognition provide a unique opportunity to study the mechanisms of neurodevelopmental disorders through the examination of genetic defects in animals and development of hypotheses that can be tested in human beings. Tuberous sclerosis complex (TSC) is a genetic disease that presents with epilepsy, autism, and intellectual disability. Here we review recent advances in our understanding of TSC pathogenesis and signaling pathways that may be modulated to treat the neurological symptoms.Recent findingsAccumulating evidence suggests that TSC patients have nontuber abnormalities that contribute to the development of the neurological phenotype - in particular, disorganization of axon tracts and deficient myelination. TSC mouse models have failed to replicate the human neuropathology entirely, but have shed light on the cellular abnormalities and the neurobehavioral phenotypes. Most importantly, cell culture and animal models have identified the mTORC1 pathway as a therapeutic target in this disease.SummaryPreclinical data strongly suggest that TSC is a disease of abnormal neuronal connectivity. The high incidence of neurodevelopmental deficits, early detection of the disease in very young ages, and availability of mTORC1 inhibitors make TSC a model for other Mendelian disorders of neurocognition and an avenue for the mechanism-based treatment trials of neurodevelopmental disorders.