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）：自闭症是一种毁灭性的疾病，对患者、他们的家庭和国家经济造成了重大损失。没有治疗方法