Molecular mechanisms of a neurodevelopmental seizure disorder

项目摘要 扰乱神经发育过程会导致一系列神经、精神和行为方面的疾病， 紊乱在美国，六分之一的儿童表现出某种形式的神经发育障碍， 从严重的功能障碍到轻微的社交行为障碍遗传学起着关键作用，许多基因 被认为是多种神经发育障碍的危险因素。然而，共同的主题是， 包括自噬-溶酶体途径的紊乱 以及mTORC 1激酶信号的失调。神经发育障碍的常见合并症 影响自噬-溶酶体途径和mTORC 1失调的突变是癫痫发作，这意味着 这些基本的细胞过程也是兴奋性和抑制性活动失衡的基础。的 该项目的目标是揭示自噬-溶酶体途径与 mTORC 1失调导致神经发育障碍和癫痫。在酵母中，我们发现 酵母Kctd（Whi 2蛋白/Whi 2 p）是TORC 1的有效负调节剂，并且是诱导 低营养条件下的自噬。基于酵母模型的发现，我们鉴定了哺乳动物 作为一个未充分研究的人类基因家族，称为钾通道四聚体， 结构域蛋白（KCTD）。酵母Kctd（Whi 2）的长期确立的结合配偶体是酵母蛋白 磷酸酶Psr 1和Psr 2，它们具有明显的人类同源物，CTDSP/CSP磷酸酶家族。我们 将测试KCTD家族蛋白是蛋白质质量控制途径的调节剂这一假设， 连接到mTORC 1信号通路。KCTD家族的几名成员与 神经发育障碍，包括癫痫、自闭症和精神分裂症。我们建议将我们的 从酵母研究中获得的独特见解，描绘了致病的重要分子机制， 使用细胞和生物化学方法和小鼠模型来重现大脑的重要方面， 人类疾病

Project Summary Disrupting neurodevelopmental processes leads to a range of neurological, psychiatric and behavioral disorders. In the US, one in six children exhibit some form of neurodevelopmental disorder, ranging from severe dysfunction to mild social-behavioral difficulties. Genetics plays a critical role and many genes have been implicated as risk factors for diverse neurodevelopmental disorders. However, common themes that are shared by multiple neurodevelopmental disorders include disturbances to the autophagy-lysosome pathway and the dysregulation of mTORC1 kinase signaling. A common co-morbidity of neurodevelopmental disorders with mutations affecting the autophagy-lysosome pathway and mTORC1 dysregulation are seizures, implying that these fundamental cellular processes also underlie an imbalance in excitatory and inhibitory activities. The goal of this project is to uncover a new molecular connection between the autophagy-lysosome pathway and mTORC1 dysregulation that leads to neurodevelopmental disorders and epilepsy. In yeast we found that the yeast Kctd (Whi2 protein/Whi2p) is a potent negative regulator of TORC1 and is required for induction of autophagy in low nutrient conditions. Based on findings from yeast models, we identified mammalian counterparts as a family of understudied human genes known as the potassium channel tetramerization domain proteins (KCTDs). The long-established binding partners of yeast Kctd (Whi2) are the yeast protein phosphatases Psr1 and Psr2, which have obvious human homologs, the CTDSP/CSP phosphatase family. We will test the hypothesis that KCTD family proteins are regulators of a protein quality control pathway that is also connected to the mTORC1 signaling pathway. Several KCTD family members have been linked to neurodevelopmental disorders including epilepsies, autism and schizophrenia. We propose to translate our unique insights gained from studies in yeast to delineate an important molecular mechanism of pathogenesis in the brain using cellular and biochemical approaches and a mouse model that recapitulates important aspects human disease.