Convergent mechanisms for neurodevelopmental disorder genes

神经发育障碍基因的趋同机制

• 批准号: 10275804
• 负责人: Kevin J Bender
• 金额: $ 55.69万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-14 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275804
• 关键词: ANK2 gene; ANK3 gene; ASD patient; Actins; Action Potentials; Affect; Amino Acids; Ankyrins; Axon; Binding; Biochemical; Biological Assay; Brain; Calcium; Cell Adhesion Molecules; Collaborations; Collection; Communities; Complementary DNA; Confocal Microscopy; Cytoskeleton; Data; Dendrites; Development; Disease; Electrophysiology (science); Etiology; Evoked Potentials; Family; Family member; Functional disorder; Gene Family; Generations; Genes; Heterozygote; Human; Image; Imaging Techniques; Immunoprecipitation; Impairment; In Vitro; Ion Channel; Knock-out; Length; Life; Ligation; Light; Link; Membrane; Modeling; Molecular; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Participant; Pathway interactions; Patients; Phenocopy; Play; Population; Protein Isoforms; Publishing; Pyramidal Cells; Role; Scaffolding Protein; Sodium; Sodium Channel; Symptoms; Synapses; Synaptic plasticity; Testing; Therapeutic Intervention; Variant; Work; autism spectrum disorder; autistic children; base; de novo mutation; early onset; excitatory neuron; exome; exome sequencing; falls; genetic variant; hippocampal pyramidal neuron; human disease; imaging approach; insight; interest; link protein; loss of function; member; molecular array; neocortical; neuronal excitability; new therapeutic target; novel; postsynaptic; repetitive behavior; risk variant; scaffold; social communication; synaptic function; transmission process; two photon microscopy; voltage

Thanks to the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). What is currently missing is a mechanism linking these genes into a convergent pathway that gives insight into disease etiology. In this proposal, we will test the hypothesis that ANK2 and SCN2A, two of the top genes implicated in ASD, are linked at the molecular level to control dendritic excitability. NaV1.2, product of the SCN2A gene, is a voltage-gated sodium channel found primarily in pyramidal neurons where it localizes to the axon initial segment (AIS) early in development. Later in development, NaV1.2 relocalizes to dendrites where it plays critical roles in synaptic plasticity and stability. The timing of the subcellular relocalization of NaV1.2 away from the AIS (~ 1 year in humans) also correlates with the onset of symptoms in ASD patients, suggesting that understanding the new role for NaV1.2 in dendrites may be critical for determining the etiology of SCN2A-associated ASD. While our group and others have shown that the intracellular scaffolding protein, ankyrin-G (ANK3), is necessary for NaV1.2 localization to the AIS, very little is known about the mechanisms underlying the dendritic localization of NaV1.2. Ankyrin-B, product of the ANK2 gene, is a member of the ankyrin gene family that shares significant homology with ankyrin-G, yet it is localized at high levels to dendrites where it may play a key role in NaV1.2 dendritic localization. Testing the hypothesis that ANK2 and SCN2A are linked at the molecular level to control dendritic excitability will have a positive impact by increasing our understanding of the mechanisms underlying synaptic alterations in ASD, which may provide novel targets for therapeutic intervention.

感谢Simons Simplex Collection，科学界拥有数十种高度可靠的风险 通过在自闭症谱系障碍(ASD)患者中识别罕见的从头基因变异。什么 目前缺失的是一种将这些基因连接到一条汇聚路径的机制，该机制可以洞察疾病 病因学。在这项提议中，我们将检验ANK2和SCN2A这两个与 ASD在分子水平上连接在一起，以控制树突状细胞的兴奋性。NaV1.2是SCN2A基因的产物，是一种 电压门控性钠通道主要存在于锥体神经元中，定位于轴突起始段 (人工智能)处于早期发展阶段。在开发的后期，NaV1.2重新定位到树突，在树突中扮演关键角色 突触的可塑性和稳定性。NAV1.2离开AIS的亚细胞重新定位的时间(~1年 在人类中)也与ASD患者症状的出现相关，这表明理解新的 NaV1.2在树突中的作用可能是确定SCN2A相关ASD病因学的关键。而我们的 小组和其他人已经证明，细胞内的支架蛋白Ankyrin-G(ANK3)是NaV1.2所必需的 对于AIS的定位，人们对NaV1.2树枝状定位的机制知之甚少。 Ankyrin-B是ANK2基因的产物，是ankyrin基因家族的成员，具有显著的同源性 在Ankyrin-G中，它定位于高水平的树突，在NaV1.2树突中可能发挥关键作用 本地化。验证ANK2和SCN2A在分子水平上连接以控制树突状细胞的假设 兴奋性将通过增加我们对突触潜在机制的理解而产生积极的影响 ASD的改变，这可能为治疗干预提供新的靶点。