Modeling the Neuropathology of Tuberous Sclerosis with Human Stem Cells Reveals a Role for Inflammation and Angiogenic Growth Factors [Cell Model]

Tuberous sclerosis complex (TSC) is a rare genetic disease characterized by mTOR hyperfunction induced benign tumor growths in multiple organs and neurological symptoms. Because the molecular pathology is highly complex and the etiology poorly understood we employed a defined human neuronal model with a single mTOR activating mutation to dissect the disease-relevant molecular responses driving the neuropathology. TSC2 deficient neural stem cells showed severely reduced neuronal functional maturation and characteristics of astrogliosis instead. Accordingly, transcriptome analysis uncovered an inflammatory response and increased metabolic activity, while ribosome profiling revealed excessive translation of ribosomal transcripts and higher synthesis rates of angiogenic growth factors. Treatment with mTOR inhibitors corrected translational alterations but not transcriptional dysfunction. These results extend our understanding of the molecular pathophysiology of TSC brain lesions, and suggest phenotype-tailored pharmacological treatment strategies.

结节性硬化症复合体（Tuberous sclerosis complex, TSC）是一种罕见的遗传性疾病，以哺乳动物雷帕霉素靶蛋白（mTOR）功能亢进引发的多器官良性肿瘤增生及神经症状为特征。鉴于该疾病的分子病理机制极为复杂，且病因尚未明确，本研究构建了携带单一mTOR激活突变的标准化人类神经元模型，以解析驱动神经病理发生的疾病相关分子应答。结节性硬化症2基因（TSC2）缺陷型神经干细胞不仅神经元功能成熟程度严重受损，反而表现出星形胶质细胞增生（astrogliosis）的特征。相应地，转录组分析（transcriptome analysis）揭示了炎症应答与代谢活性上调；而核糖体谱分析（ribosome profiling）则发现核糖体转录本的翻译过程过度激活，血管生成生长因子的合成速率也显著升高。采用mTOR抑制剂进行干预可纠正翻译层面的异常，但无法改善转录功能障碍。本研究结果深化了我们对TSC脑部病变分子病理生理学的认识，并提示了基于表型定制的药物治疗策略。