Feliciano David M
Department of Biological Sciences, Clemson University, Clemson, SC, United States.
Front Neuroanat. 2020 Jul 14;14:39. doi: 10.3389/fnana.2020.00039. eCollection 2020.
Tuberous sclerosis complex (TSC) is a model disorder for understanding brain development because the genes that cause TSC are known, many downstream molecular pathways have been identified, and the resulting perturbations of cellular events are established. TSC, therefore, provides an intellectual framework to understand the molecular and biochemical pathways that orchestrate normal brain development. The TSC1 and TSC2 genes encode Hamartin and Tuberin which form a GTPase activating protein (GAP) complex. Inactivating mutations in TSC genes (TSC1/TSC2) cause sustained Ras homologue enriched in brain (RHEB) activation of the mammalian isoform of the target of rapamycin complex 1 (mTORC1). TOR is a protein kinase that regulates cell size in many organisms throughout nature. mTORC1 inhibits catabolic processes including autophagy and activates anabolic processes including mRNA translation. mTORC1 regulation is achieved through two main upstream mechanisms. The first mechanism is regulation by growth factor signaling. The second mechanism is regulation by amino acids. Gene mutations that cause too much or too little mTORC1 activity lead to a spectrum of neuroanatomical changes ranging from altered brain size (micro and macrocephaly) to cortical malformations to Type I neoplasias. Because somatic mutations often underlie these changes, the timing, and location of mutation results in focal brain malformations. These mutations, therefore, provide gain-of-function and loss-of-function changes that are a powerful tool to assess the events that have gone awry during development and to determine their functional physiological consequences. Knowledge about the TSC-mTORC1 pathway has allowed scientists to predict which upstream and downstream mutations should cause commensurate neuroanatomical changes. Indeed, many of these predictions have now been clinically validated. A description of clinical imaging and histochemical findings is provided in relation to laboratory models of TSC that will allow the reader to appreciate how human pathology can provide an understanding of the fundamental mechanisms of development.
结节性硬化症（TSC）是一种用于理解大脑发育的典型疾病，因为导致TSC的基因已为人所知，许多下游分子途径已被确定，并且由此产生的细胞事件扰动也已明确。因此，TSC为理解协调正常大脑发育的分子和生化途径提供了一个知识框架。TSC1和TSC2基因编码错构瘤蛋白和结节蛋白，它们形成一种GTP酶激活蛋白（GAP）复合物。TSC基因（TSC1/TSC2）的失活突变会导致大脑中富集的Ras同源物（RHEB）持续激活雷帕霉素复合物1（mTORC1）的哺乳动物异构体。TOR是一种蛋白激酶，在自然界中许多生物体中调节细胞大小。mTORC1抑制包括自噬在内的分解代谢过程，并激活包括mRNA翻译在内的合成代谢过程。mTORC1的调节通过两种主要的上游机制实现。第一种机制是由生长因子信号传导调节。第二种机制是由氨基酸调节。导致mTORC1活性过高或过低的基因突变会导致一系列神经解剖学变化，从大脑大小改变（小头畸形和巨头畸形）到皮质畸形再到I型肿瘤形成。由于体细胞突变往往是这些变化的基础，突变的时间和位置会导致局灶性脑畸形。因此，这些突变提供了功能获得和功能丧失的变化，这是评估发育过程中出错的事件并确定其功能生理后果的有力工具。关于TSC-mTORC1途径的知识使科学家能够预测哪些上游和下游突变会导致相应的神经解剖学变化。事实上，现在许多这些预测已经在临床上得到验证。本文提供了与TSC实验室模型相关的临床影像学和组织化学研究结果的描述，这将使读者了解人类病理学如何有助于理解发育的基本机制。
