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: 8823213
• 负责人: JULIE C LAUTERBORN
• 金额: $ 23.18万
• 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 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8823213
• 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; Elements; Estrogen Receptor beta; Excitatory Synapse; Exhibits; F-Actin; Family; Fluorescence; Fragile X Syndrome; Guanosine Triphosphate Phosphohydrolases; 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; human EMS1 protein; improved; insight; memory encoding; middle age; mouse Ts65Dn; mouse model; neurochemistry; oncoprotein p21; p21 activated kinase; polymerization; postsynaptic; preclinical study; public health relevance; receptor; rho; rho GTP-Binding Proteins; synaptic function; 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）：脊柱紊乱是唐氏综合症 (DS) 等智力发育障碍 (IDD) 的一个常见特征，大约每 700 名活产儿中就有 1 人患有这种疾病，并且与平均 IQ 为 50 相关。在 DS 中，皮质树突棘通常被描述为显得不成熟（长、薄且曲折），并且树突棘密度降低。这些形态学紊乱背后的细胞机制尚不清楚，但可能涉及脊柱肌动蛋白细胞骨架的失调，这在很大程度上决定了脊柱的形状，并且对于记忆编码的可塑性至关重要。我们之前的工作表明，在另一种 IDD（脆性 X 综合征）的小鼠模型中，参与调节脊柱丝状 (F-) 肌动蛋白的 Rho 家族 GTP 酶通路（Rac 级联）的功能明显受到干扰；这与一些 IDD 在 Rho GTPase 通路中表现出异常的观察结果一致。然而，尚不清楚脊柱 Rho GTPase 信号传导的特定缺陷在 IDD 之间共享的程度或在直接调节脊柱 F-肌动蛋白的相同下游蛋白上的收敛程度。在使用荧光解卷积显微镜的初步研究中，我们评估了中年人 DS 顶叶皮质中的两种 Rac 通路蛋白：p21 激活激酶 3 (PAK3) 和 Arp2。结果表明，兴奋性 PSD95 免疫阳性 (+) 突触中两种蛋白的水平均降低，表明 DS 中肌动蛋白调节机制确实受到干扰。结果还表明，与脆性 X 综合征一样，DS 表现出特定于调节脊柱肌动蛋白网络的分支和稳定性的 Rac 级联的异常。拟议的研究将扩展这些发现，并检验三体性导致 DS 导致树突棘紊乱的假设 Rac GTPase 级联，而 RhoA 级联中的元件相对正常。目标 1 研究将进一步测试肌动蛋白调节蛋白的异常是否存在于整个年龄范围的 DS 个体中或优先在较晚的年龄，以及这些扰动是否在患有阿尔茨海默病 (AD) tau 病理学的 DS 个体中最为严重。研究结果将提供关于肌动蛋白信号传导紊乱是否是 DS 的核心特征，还是继发于 AD 病理的继发性见解。然后，目标 2 将测试 DS 的 Ts65Dn 小鼠模型中是否存在 Rac 通路蛋白异常，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，该研究旨在设计治疗方法来弥补 DS 中的脊柱缺陷并促进学习。与此相关，我们已经证明，通过几种突触调节受体操纵信号传导可以显着改变局部肌动蛋白调节信号传导，并且在某些情况下，可以恢复受损动物的正常肌动蛋白重塑、突触可塑性和认知功能。因此，拟议的研究将确定 DS 棘中是否存在肌动蛋白调节缺陷，这可能对基于肌动蛋白的认知增强策略有类似的反应。