Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Department of Pharmaceutical Sciences, Università del Piemonte Orientale "Amedeo Avogadro", Novara, Italy.
Acta Neuropathol. 2024 Feb 28;147(1):48. doi: 10.1007/s00401-024-02711-3.
Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors in various organs, including the brain, and is often accompanied by epilepsy, neurodevelopmental comorbidities including intellectual disability and autism. A key hallmark of TSC is the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, which induces alterations in cortical development and metabolic processes in astrocytes, among other cellular functions. These changes could modulate seizure susceptibility, contributing to the progression of epilepsy and its associated comorbidities. Epilepsy is characterized by dysregulation of calcium (Ca) channels and intracellular Ca dynamics. These factors contribute to hyperexcitability, disrupted synaptogenesis, and altered synchronization of neuronal networks, all of which contribute to seizure activity. This study investigates the intricate interplay between altered Ca dynamics, mTOR pathway dysregulation, and cellular metabolism in astrocytes. The transcriptional profile of TSC patients revealed significant alterations in pathways associated with cellular respiration, ER and mitochondria, and Ca regulation. TSC astrocytes exhibited lack of responsiveness to various stimuli, compromised oxygen consumption rate and reserve respiratory capacity underscoring their reduced capacity to react to environmental changes or cellular stress. Furthermore, our study revealed significant reduction of store operated calcium entry (SOCE) along with strong decrease of basal mitochondrial Ca concentration and Ca influx in TSC astrocytes. In addition, we observed alteration in mitochondrial membrane potential, characterized by increased depolarization in TSC astrocytes. Lastly, we provide initial evidence of structural abnormalities in mitochondria within TSC patient-derived astrocytes, suggesting a potential link between disrupted Ca signaling and mitochondrial dysfunction. Our findings underscore the complexity of the relationship between Ca signaling, mitochondria dynamics, apoptosis, and mTOR hyperactivation. Further exploration is required to shed light on the pathophysiology of TSC and on TSC associated neuropsychiatric disorders offering further potential avenues for therapeutic development.
结节性硬化症（TSC）是一种多系统遗传疾病，其特征是在包括大脑在内的各种器官中形成良性肿瘤，并且常伴有癫痫、神经发育合并症，包括智力障碍和自闭症。TSC 的一个关键标志是雷帕霉素（mTOR）信号通路的过度激活，这会导致皮质发育和星形胶质细胞代谢过程的改变，以及其他细胞功能的改变。这些变化可能会调节癫痫易感性，导致癫痫及其相关合并症的进展。癫痫的特征是钙（Ca）通道和细胞内 Ca 动力学的失调。这些因素导致兴奋性过高、突触形成障碍以及神经元网络的同步改变，所有这些都导致癫痫发作。本研究探讨了星形胶质细胞中 Ca 动力学改变、mTOR 通路失调和细胞代谢之间的复杂相互作用。TSC 患者的转录谱显示，与细胞呼吸、内质网和线粒体以及 Ca 调节相关的途径发生了显著改变。TSC 星形胶质细胞对各种刺激的反应能力下降，氧消耗率和储备呼吸能力受损，这表明它们对环境变化或细胞应激的反应能力降低。此外，我们的研究还揭示了 TSC 星形胶质细胞中储存操作钙内流（SOCE）显著减少，基础线粒体 Ca 浓度和 Ca 内流明显降低。此外，我们观察到 TSC 星形胶质细胞中线粒体膜电位发生改变，表现为去极化增加。最后，我们提供了 TSC 患者来源的星形胶质细胞中线粒体结构异常的初步证据，表明 Ca 信号传导和线粒体功能障碍之间存在潜在联系。我们的发现强调了 Ca 信号传导、线粒体动力学、细胞凋亡和 mTOR 过度激活之间关系的复杂性。需要进一步探索以阐明 TSC 的病理生理学和 TSC 相关神经精神障碍，为治疗开发提供进一步的潜在途径。
