Cortactin and Spine Dysfunction in Fragile X

脆性 X 细胞的 Cortactin 和脊柱功能障碍

• 批准号: 8317096
• 负责人: Ronald Robert Seese
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-10 至 2016-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317096
• 关键词: Accounting; Acetylation; Actins; Actomyosin; Acute; Adult; Affect; Anatomy; Angelman Syndrome; Animals; Attenuated; Autistic Disorder; Cell physiology; Cells; Characteristics; Cognitive; Cognitive deficits; Comorbidity; Cytoskeleton; Defect; Dendritic Spines; Depressed mood; Development; Disease; Event; Exhibits; F-Actin; Failure; Family; Fragile X Syndrome; Functional disorder; GTP Binding; Guanosine Triphosphate Phosphohydrolases; HDAC6 gene; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Knock-out; Knockout Mice; Laboratories; Learning; Location; Long-Term Potentiation; MAP Kinase Gene; Measures; Mediating; Memory; Memory impairment; Microtubules; Mitogen-Activated Protein Kinase Kinases; Mitogens; Modeling; Modification; Molecular; Monomeric GTP-Binding Proteins; Morphology; Movement; Mus; Neurobiology; Neurons; Pathway interactions; Patients; Pattern; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Process; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Public Health; Regulation; Regulatory Pathway; Research; Serine; Signal Pathway; Signal Transduction; Slice; Stream; Synapses; Synaptic plasticity; Synaptosomes; System; Testing; Therapeutic; Vertebral column; Work; autism spectrum disorder; base; cognitive function; cost; genetic regulatory protein; histone deacetylase 6; human EMS1 protein; improved; in vivo; innovative technologies; interest; memory encoding; memory recognition; mouse model; mutant; novel; p21 activated kinase; prevent; success; therapeutic target; trafficking; transmission process

DESCRIPTION (provided by applicant): Autism is a devastating condition which takes a significant toll on patients, their families, and the national economy. There are no treatments for cognitive impairments (e.g., learning and memory deficits) that affect over 75% of autistic patients. In models of many autism-associated disorders and conditions with comorbidity for autism, such Fragile X, Rett, and Angelman Syndromes, there are significant abnormalities in dendritic spine morphology, which are associated with impairments in the stabilization of long-term potentiation (LTP), a synaptic mechanism of memory encoding. Together, these findings suggest that defects in the spine actin cytoskeleton may underlie cognitive deficits in autism-associated conditions of different origin. Spine abnormalities and LTP impairments are best characterized in the Fmr1-knockout (KO) mouse model of fragile X syndrome (FXS), a condition with high (~30%) comorbidity for autism. Specifically, these mutants exhibit defects in signaling through Rac GTPase, stabilization of activity-driven changes in spine filamentous (F) actin, and consolidation of LTP. Studies by the applicant have demonstrated that movement of cortactin, a spine protein which stabilizes actin network branch points and protects F-actin from degradation, via both actomyosin and microtubule systems, is impaired at Fmr1-KO spines following LTP-induction. This suggests that the F- actin stabilization deficits in KOs may reflect disturbances in signaling to cortactin. The proposed research will build on these findings to test the specific hypotheses that (a) abnormal cortactin serine phosphorylation and acetylation, which regulate the protein's subcellular movement, both originate from a single molecular impairment and contribute to the phenotype of impaired movement following LTP induction in KOs and that (b) learning (in vivo) activates these synaptic processes in WT but not KO mice. There are 3 specific aims. Aim 1 will test if basal levels or activation of synaptic Ras or PP2A are impaired in KOs (both of these targets influence the cortactin phosphorylation and acetylation paths). Aim 2 will test if signaling through MAPK and/or HDAC6, which contribute to cortactin serine phosphorylation and acetylation, are necessary for activity- induced cortactin translocation. hippocampus-dependent spatial learning activates synaptic signaling to cortactin in the WTs and if this signaling is attenuated or absent in Fmr1-KOs in vivo. Through interrogating synaptic mechanisms associated with impairments in F-actin stabilization and determining if these abnormalities are also present in the behaving animal, the proposed studies will contribute to our understanding of synaptic plasticity in both normal and FXS model mice and offer therapeutic targets for normalization of memory function in FXS and other autistic conditions. Finally, Aim 3 will test if hippocampus-dependent spatial learning activatessynaptic signaling to cortactin in the WTs and if this signaling is attenuated or absent in Fmr1-KOs in vivo. Through interrogating synaptic mechanisms associated with impairments in F-actin stabilization and determining if these abnormalities are also present in the behaving animal, the proposed studies will contribute to our understanding of synaptic plasticity in both normal and FXS model mice and offer therapeutic targets for normalization of memory function in FXS and other autistic conditions. PUBLIC HEALTH RELEVANCE: There are no available therapeutics for the cognitive component (e.g. learning and memory impairments) of autism, a disease with increasing incidence and staggering national costs. Building upon novel findings that stabilization of the actin cytoskeleton is abnormal in a mouse model of a disease highly associated with autism, fragile X syndrome, the proposed research will test the hypotheses that modulation of the actin-associated protein cortactin is impaired in fragile X model mice and that these regulatory pathways are critically involved in the protein's cellular functions that are engaged during learning. This work is directly relevant to public health issues by advancing our understanding of cellular processes underlying cognitive impairment with autism, a highly prevalent condition with no known cure. Moreover, and importantly, these studies are expected to identify important therapeutic targets for improving cognitive (learning) function in fragile X syndrome and potentially other autism associated disorders.

描述（由申请人提供）：自闭症是一种破坏性的状况，对患者，家人和国民经济造成了重大损失。没有治疗 影响超过75％的自闭症患者的认知障碍（例如学习和记忆缺陷）。在许多自闭症相关疾病和有合并症的自闭症的模型中，这种脆弱的X，RETT和Angelman综合症，树突状脊柱形态存在明显的异常，这与长期增强（LTP）稳定的损害有关，一种记忆编码的突触机制。总之，这些发现表明脊柱肌动蛋白细胞骨架中的缺陷可能是不同来源的自闭症相关条件下的认知缺陷。脊柱异常和LTP损伤是脆弱X综合征（FXS）的FMR1-KNOCKOUT（KO）小鼠模型，这是一种自闭症的较高（约30％）的疾病。具体而言，这些突变体在通过RAC GTPase，脊柱丝（F）肌动蛋白（F）肌动蛋白的活性驱动变化以及LTP巩固的信号传导中表现出缺陷。申请人的研究表明，在LTP诱导后，在FMR1-KO棘上受损，稳定肌动蛋白网络分支点并保护肌动蛋白网络分支点并保护F-肌动蛋白免受降解的脊柱运动。这表明KOS中的F-肌动蛋白稳定缺陷可能反映了对Cortactin的信号传导的干扰。拟议的研究将基于这些发现以检验（a）（a）调节蛋白质亚细胞运动的特定假设，即（a）皮质素丝氨酸磷酸化和乙酰化的异常，均来自单个分子损伤，并有助于LTP诱导的表型在LTP诱导的表型中的损害。 KOS和（b）学习（体内）在WT中激活这些突触过程，但没有激活KO小鼠。有3个具体目标。 AIM 1将测试KOS中突触RAS或PP2A的基础水平或激活是否受损（这两个靶标都会影响皮质素磷酸化和乙酰化路径）。 AIM 2将测试通过MAPK和/或HDAC6信号传导是否有助于皮质素丝氨酸磷酸化和乙酰化，对于活性诱导的cortactin易位是必需的。海马依赖性的空间学习激活了WTS中皮尔塔辛的突触信号传导，如果在体内fmr1-kos中衰减或不存在此信号。通过询问与F-肌动蛋白稳定损伤相关的突触机制，并确定行为动物中是否也存在这些异常，拟议的研究将有助于我们理解正常和FXS模型小鼠突触可塑性的理解，并为治疗目标提供治疗目标FXS和其他自闭症条件中的内存功能。最后，AIM 3将测试Hippocampus依赖的空间学习激活信号在WTS中向Cortactin，以及该信号是否在体内减弱或不存在。通过询问与F-肌动蛋白稳定损伤相关的突触机制，并确定行为动物中是否也存在这些异常，拟议的研究将有助于我们理解正常和FXS模型小鼠突触可塑性的理解，并为治疗目标提供治疗目标FXS和其他自闭症条件中的内存功能。 公共卫生相关性：自闭症的认知成分（例如学习和记忆障碍）没有可用的治疗方法，这种疾病的发病率和破坏性的国家成本增加。基于新的发现，即肌动蛋白细胞骨架的稳定在与自闭症，脆弱X综合征高度相关的疾病的小鼠模型中是异常小鼠，这些调节途径与学习过程中参与的蛋白质的细胞功能非常重要。这项工作与公共卫生问题直接相关，通过促进我们对自闭症认知障碍潜在的细胞过程的理解，这是一种高度普遍的疾病，没有已知的治愈方法。此外，重要的是，这些研究有望确定重要的治疗靶标，以改善脆弱X综合征的认知功能（学习）功能，并可能与其他自闭症相关的疾病。