Molecular mechanisms of a neurodevelopmental seizure disorder

神经发育性癫痫病的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要扰乱神经发育过程会导致一系列神经、精神和行为问题失调。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困难。遗传学起着至关重要的作用，许多基因都具有被认为是多种神经发育障碍的危险因素。然而，共同的主题是多种神经发育障碍所共有的疾病包括自噬-溶酶体途径的紊乱以及 mTORC1 激酶信号传导失调。神经发育障碍的常见共病影响自噬-溶酶体途径的突变和 mTORC1 失调会导致癫痫发作，这意味着这些基本的细胞过程也是兴奋性和抑制性活动不平衡的基础。这该项目的目标是揭示自噬-溶酶体途径和 mTORC1 失调会导致神经发育障碍和癫痫。在酵母中我们发现酵母 Kctd（Whi2 蛋白/Whi2p）是 TORC1 的有效负调节因子，是诱导低营养条件下的自噬。根据酵母模型的研究结果，我们确定了哺乳动物对应物是一个未被研究的人类基因家族，称为钾通道四聚化结构域蛋白（KCTD）。酵母 Kctd (Whi2) 的长期结合伙伴是酵母蛋白磷酸酶 Psr1 和 Psr2，具有明显的人类同源物，即 CTDSP/CSP 磷酸酶家族。我们将检验以下假设：KCTD 家族蛋白是蛋白质质量控制途径的调节剂，该途径也是与 mTORC1 信号通路相连。多名 KCTD 家族成员与神经发育障碍，包括癫痫、自闭症和精神分裂症。我们建议翻译我们的从酵母研究中获得的独特见解，描绘了致病机制的重要分子机制使用细胞和生化方法以及概括重要方面的小鼠模型来研究大脑人类疾病。