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：
10597690
负责人：
J. Marie Hardwick
金额：
$ 24.56万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10597690
关键词：
Affect 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 Homologous Gene 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 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 model organism 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.

项目摘要破坏神经发育过程会导致一系列神经，精神病和行为疾病。在美国，六分之一的孩子表现出某种形式的神经发育障碍，从严重的对轻度社会行为困难的功能障碍。遗传学起着至关重要的作用，许多基因具有被认为是不同神经发育障碍的风险因素。但是，常见的主题是多种神经发育障碍共享包括对自噬溶质体途径的干扰 MTORC1激酶信号传导的失调。神经发育障碍的常见合并症随着影响自噬溶质体途径和MTORC1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活性失衡的基础。这该项目的目标是揭示自噬溶质体途径和 MTORC1失调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的有效调节剂，是诱导的在低营养条件下自噬。根据酵母模型的发现，我们确定了哺乳动物对应物是一个被研究的人类基因的家族，称为钾通道四聚体结构蛋白（KCTD）。酵母KCTD（WHI2）的长期结合伴侣是酵母蛋白磷酸酶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，也是连接到MTORC1信号通路。几个KCTD家庭成员已链接到神经发育障碍，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，以描绘出一种重要的发病机理的分子机制使用细胞和生化方法的大脑以及概括重要方面的小鼠模型人类疾病。