Molecular mechanisms of a neurodevelopmental seizure disorder

神经发育性癫痫病的分子机制

• 批准号: 10433302
• 负责人: J. Marie Hardwick
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433302
• 关键词: Affect; Animal Model; Autophagocytosis; BTB/POZ Domain; Behavior Disorders; Behavioral; Binding; Biochemical; Biological Assay; Brain; CLN14 gene; Cell Death; Cell physiology; Cells; Child; Complex; Cytoplasmic Tail; Data; Defect; Development; Developmental Delay Disorders; Disease; Down-Regulation; Epilepsy; Exhibits; FRAP1 gene; Family; Family member; Functional disorder; Gene Family; Genes; Genetic; Goals; Human; In Vitro; Link; Lysosomes; Mammals; Mental disorders; Modeling; Molecular; Movement Disorders; Mus; Mutation; N-terminal; Names; Neurodevelopmental Disorder; Neuronal Ceroid-Lipofuscinosis; Neurons; Nutrient; Pathogenesis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Play; Potassium Channel; Process; Protein Family; Protein phosphatase; Proteins; Quality Control; RNA; Reporting; Risk Factors; Role; Saccharomyces cerevisiae; Schizophrenia; Seizures; Signal Pathway; Signal Transduction; Synapses; Tertiary Protein Structure; Testing; Translating; Transmembrane Domain; Ubiquitination; Variant; Work; Yeast Model System; Yeasts; autism spectrum disorder; base; biological adaptation to stress; comorbidity; cullin-3; detection of nutrient; developmental disease; early onset; gamma-Aminobutyric Acid; human disease; inhibitory neuron; insight; loss of function mutation; member; mouse model; mutant; nervous system disorder; neuron development; novel; patient subsets; receptor; recruit; social; transcription factor; ubiquitin-protein ligase; yeast protein

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.

项目摘要 扰乱神经发育过程导致一系列神经学、精神病学和行为学 精神错乱。在美国，六分之一的儿童表现出某种形式的神经发育障碍，范围从 严重的功能障碍到轻微的社交行为困难。遗传学起着关键作用，许多基因都有 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 由多种神经发育障碍所共有，包括自噬-溶酶体途径障碍 以及mTORC1K信号通路的失调。神经发育障碍的常见并存 影响自噬-溶酶体途径的突变和mTORC1调节失调是癫痫，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。这个 该项目的目标是发现自噬-溶酶体途径和自噬-溶酶体途径之间的新的分子联系 MTORC1失调，导致神经发育障碍和癫痫。在酵母中，我们发现 酵母菌Kctd(Whi2蛋白/Whi2p)是一种强有力的TORC1负调控因子，是诱导 低营养条件下的自噬。基于酵母模型的发现，我们识别了哺乳动物 作为一个被称为钾通道四聚化的未被研究的人类基因家族 结构域蛋白(KCTD)。酵母Kctd(WHI2)长期存在的结合伙伴是酵母蛋白 磷酸酶Psr1和Psr2是CTDSP/CSP磷酸酶家族，与人类有明显的同源性。我们 将检验KCTD家族蛋白是蛋白质质量控制途径的调节者这一假设 连接到mTORC1信号通路。几个KCTD家族成员被认为与 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 在酵母菌研究中获得的独特见解，以描绘一种重要的致病分子机制 使用细胞和生化方法的大脑和概括重要方面的小鼠模型 人类疾病。