Synaptic Actin Regulatory Proteins in Down Syndrome

唐氏综合症中的突触肌动蛋白调节蛋白

• 批准号: 9039113
• 负责人: JULIE C LAUTERBORN
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9039113
• 关键词: Actins; Address; Adenosine; Affect; Age; Alzheimer' s Disease; Animal Model; Animals; Cytoskeleton; DLG4 gene; Defect; Dendritic Spines; Depressed mood; Disease; Down Syndrome; EMS1 gene; Elements; Estrogen Receptor beta; Excitatory Synapse; Exhibits; F-Actin; Family; Fluorescence; Fragile X Syndrome; Guanosine Triphosphate Phosphohydrolases; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; Incidence; Independent Living; Indium; Individual; Intellectual functioning disability; Learning; Left; Live Birth; Microscopy; Modeling; Neocortex; Neurotrophic Tyrosine Kinase Receptor Type 2; Parietal Lobe; Pathology; Pathway interactions; Process; Proteins; Regulation; Scaffolding Protein; Secondary to; Shapes; Signal Transduction; Signaling Protein; Stream; Synapses; Synaptic plasticity; Synaptophysin; System; Testing; Therapeutic; Trisomy; United States; Vertebral column; Western Blotting; Work; base; case-based; cofilin; cognitive enhancement; cognitive function; density; developmental disease; genetic regulatory protein; improved; insight; memory encoding; middle age; mouse Ts65Dn; mouse model; neurochemistry; p21 activated kinase; polymerization; postsynaptic; preclinical study; protein biomarkers; receptor; rho; rho GTP-Binding Proteins; synaptic function; targeted treatment; tau Proteins; therapeutic target; tomography

DESCRIPTION (provided by applicant): Spine disturbances are a common feature of intellectual developmental disorders (IDD) such as Down Syndrome (DS), which occurs in ~ 1 in 700 live births and is associated with an average IQ of 50. In DS, cortical dendritic spines are often described as appearing immature (long, thin and tortuous) and spine densities are reduced. The cellular mechanisms underlying these morphological disturbances are not known but likely involve dysregulation of the spine actin cytoskeleton that largely determines spine shape and is critical for plasticity underlying memory encoding. Our previous work has shown that function of one Rho-family GTPase pathway involved in regulating spine filamentous (F-) actin, the Rac cascade, is markedly disturbed in a mouse model of another IDD, Fragile X syndrome; this aligns with observations that several IDDs exhibit abnormalities in Rho GTPase pathways. However, it is not known the degree to which specific defects in spine Rho GTPase signaling are shared across IDDs or converge on the same down-stream proteins that directly regulate spine F-actin. In preliminary studies using fluorescence deconvolution microscopy, we evaluated two Rac pathway proteins, p21-activated kinase 3 (PAK3) and Arp2, in middle-aged human DS parietal cortex. The results demonstrate that levels of both proteins are reduced at excitatory, PSD95-immunopositive (+) synapses suggesting that the actin regulatory machinery is indeed disturbed in DS. The results also suggest the possibility that, like Fragile X syndrome, DS exhibits abnormalities specific to the Rac cascade that regulates the branching and stabilization of the spine actin network. The proposed studies will expand upon these findings and test the hypothesis that trisomy giving rise to DS leads to disturbances in the dendritic spine Rac GTPase cascade while leaving elements in the RhoA cascade relatively normal. Aim 1 studies will further test if abnormalities in actin regulatory proteins are present in DS individuas across a broad age range or preferentially at later ages, and if these perturbations are greatest in DS individuals with Alzheimer's Disease (AD) tau pathology. Findings will provide insight as to whether the actin signaling disturbances are core features of DS, or secondary to emergent AD pathology. Aim 2 will then test if abnormalities in Rac pathway proteins are present in the Ts65Dn mouse model of DS that exhibits both spine and synaptic plasticity abnormalities. Confirmation of this point is essential for the use of the Ts65Dn model in preclinical studies aimed at devising therapies to offset spine defects, and facilitate learning, in DS. Pertinent to this, we have shown that manipulation of signaling through several synaptic modulatory receptors can dramatically alter local actin regulatory signaling and, in some cases, restore normal actin remodeling, synaptic plasticity, and cognitive function in otherwise impaired animals. Thus, the proposed studies will determine if actin regulatory deficits are present in DS spines that might be similarly responsive to actin based strategies for cognitive enhancement.

描述（由申请人提供）：脊柱障碍是智力发育障碍（IDD）的共同特征，例如唐氏综合症（DS），在700个活产中〜1中发生，与50个平均智商相关。在DS中，皮质树突状棘突通常被描述为显得不成熟（长而薄，薄，柔软）和脊柱含量不足。这些形态学障碍的基础机制尚不清楚，但可能涉及脊柱肌动蛋白细胞骨架的失调，该骨骨骼在很大程度上决定了脊柱形状，对于记忆编码的可塑性至关重要。我们以前的工作表明，在另一个IDD，易碎X综合征的小鼠模型中，一种涉及调节脊柱丝状（F-）肌动蛋白（RAC Cascade）涉及的一个Rho-family GTPase途径的功能。这与观察到的几个IDD在Rho GTPase途径中表现出异常。但是，尚不清楚脊柱Rho GTPase信号中的特定缺陷在IDD上共享或在直接调节脊柱F-肌动蛋白的相同下游蛋白上收敛。在使用荧光反卷积显微镜的初步研究中，我们在中年人类DS顶层皮层中评估了两种RAC途径蛋白，P21激活激酶3（PAK3）和ARP2。结果表明，两种蛋白质的水平在兴奋性，PSD95-免疫阳性（+）突触时都降低，这表明肌动蛋白调节机械确实在DS中受到干扰。结果还表明，像脆弱的X综合征一样，DS表现出对RAC级联反应的异常，从而调节脊柱肌动蛋白网络的分支和稳定性。拟议的研究将扩大这些发现，并检验以下假设：三体性引起DS会导致树突状脊柱的干扰 RAC GTPase级联当将元素留在Rhoa Cascad中时相对正常。 AIM 1研究将进一步测试肌动蛋白调节蛋白的异常，在DS个体中存在众多年龄范围内的DS个体或以后的年龄优先，并且这些扰动在患有阿尔茨海默氏病（AD）TAU病理学的DS患者中是最大的。发现将提供有关肌动蛋白信号障碍是DS的核心特征还是继发于新兴AD病理学的核心。然后，AIM 2将测试RAC途径蛋白异常是否存在于DS的TS65DN小鼠模型中，该模型表现出脊柱和突触可塑性异常。确认这一点对于在临床前研究中使用TS65DN模型至关重要，旨在设计疗法以抵消脊柱缺陷，并促进DS学习。与此相关的是，我们已经表明，通过几种突触调节受体对信号的操纵可以极大地改变局部肌动蛋白调节信号传导，并在某些情况下恢复正常的肌动蛋白重塑，突触可塑性和其他受损动物的认知功能。因此，拟议的研究将确定肌动蛋白调节性缺陷是否存在于DS棘中，这可能对基于肌动蛋白的认知增强策略有类似的反应。