Neuronal: Glial Interactions Underlying Rett Syndrome

神经元：雷特综合征背后的神经胶质相互作用

• 批准号: 8279335
• 负责人: Gail Mandel
• 金额: $ 29.26万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279335
• 关键词: Adult; Affect; Astrocytes; Ataxia; Biochemical; Brain; Chromatin; Coculture Techniques; Conditioned Culture Media; Data; Defect; Disease; Employee Strikes; Exhibits; Genes; Glial Fibrillary Acidic Protein; Grant; Health; Heating; Hindlimb; Human; Messenger RNA; Methyl-CpG-Binding Protein 2; Morphology; Mus; Mutation; Nature; Nervous system structure; Neuraxis; Neuroglia; Neurons; Patients; Property; Proteins; Repression; Rett Syndrome; Role; Slice; Symptoms; Synapses; Tamoxifen; Testing; Therapeutic Intervention; Time; Two-Dimensional Gel Electrophoresis; base; brain size; chromatin modification; girls; in vivo; metallothionein III; mouse model; nervous system disorder; recombinase; research study

DESCRIPTION (provided by applicant): Rett Syndrome (RTT) is a severe neurological disorder in humans that results from mutations in the gene encoding methyl-CpG binding protein 2, MeCP2. One of the mysteries surrounding RTT is that although MeCP2 is a ubiquitous protein, the manifestations of the disease are restricted primarily to the central nervous system. Possible explanations have included increased sensitivity of neurons to loss of MeCP2 and lack of redundancy of MeCP2 function in neurons. Here we present an alternative idea, that the nervous system manifestation of RTT is due, at least in part, to loss of MeCP2 from glia, which in turn results in a negative influence on neurons. This idea is based on our preliminary findings that 1) MeCP2 is expressed in glia as well as in neurons, 2) that astroglia from RTT mice exhibit chromatin modifications similar to those in brains of mice lacking MeCP2, suggesting a less repressive chromatin status, and 3) that, in co- culture, RTT astroglia confer an aberrant morphology on wild type neurons. We will test this new idea in three specific aims. First, we will identify the defects induced in wild type (WT) neurons by astroglia from RTT mice and determine, conversely, whether defects in neurons from RTT mice are rescued by WT astroglia. Second, our conditioned medium experiments suggest that astroglia from RTT mice secrete a soluble protein inhibitory to neuronal morphology. We will analyze by microarray and biochemical approaches, the nature of the aberrant factor(s) secreted by astroglia from RTT mice. Finally, we will characterize RTT symptoms in a newly generated mouse model in which MeCP2 can be deleted either specifically from astroglia or from both neurons and astroglia. These mice will provide in vivo confirmation of a role for MeCP2-null astroglia in conferring aberrant neuronal morphology in RTT and permit functional studies of neurons in the context of abnormal astroglia. The proposed studies offer the potential for a new attack, through pharmacological inhibition of potential glial secreted inhibitory factors, on this debilitating neurological disorder that strikes one in 10,000-15,000 girls. PUBLIC HEALTH REVELANCE This grant identifies, for the first time, a potential role for a factor secreted from glia as an underlying cause of neuronal damage in Rett Syndrome. If, as our data suggest, the glial effects are due to secretion of an inhibitory growth factor, it raises the possibility of therapeutic intervention for treatment of RTT patients.

描述（由申请人提供）：雷特综合征（RTT）是一种严重的人类神经系统疾病，由编码甲基 CpG 结合蛋白 2（MeCP2）的基因突变引起。围绕 RTT 的一个谜团是，尽管 MeCP2 是一种普遍存在的蛋白质，但该疾病的表现主要限于中枢神经系统。可能的解释包括神经元对 MeCP2 丢失的敏感性增加以及神经元中 MeCP2 功能冗余的缺乏。在这里，我们提出了另一种观点，即 RTT 的神经系统表现至少部分是由于神经胶质细胞中 MeCP2 的丢失，这反过来又对神经元产生负面影响。这个想法基于我们的初步发现：1) MeCP2 在神经胶质细胞和神经元中表达，2) RTT 小鼠的星形胶质细胞表现出与缺乏 MeCP2 的小鼠大脑中类似的染色质修饰，表明染色质状态的抑制程度较低，并且3)在共培养中，RTT星形胶质细胞赋予野生型神经元异常的形态。我们将在三个具体目标上测试这个新想法。首先，我们将鉴定 RTT 小鼠星形胶质细胞在野生型 (WT) 神经元中诱导的缺陷，并反过来确定 WT 星形胶质细胞是否可以修复 RTT 小鼠神经元中的缺陷。其次，我们的条件培养基实验表明，RTT 小鼠的星形胶质细胞分泌一种可溶性蛋白，抑制神经元形态。我们将通过微阵列和生化方法分析 RTT 小鼠星形胶质细胞分泌的异常因子的性质。最后，我们将在新生成的小鼠模型中描述 RTT 症状，其中 MeCP2 可以从星形胶质细胞中特异性删除，也可以从神经元和星形胶质细胞中删除。这些小鼠将在体内证实 MeCP2 缺失的星形胶质细胞在 RTT 中赋予异常神经元形态的作用，并允许在异常星形胶质细胞的背景下对神经元进行功能研究。拟议的研究提供了通过对潜在的神经胶质分泌的抑制因子进行药理学抑制来对这种使人衰弱的神经系统疾病进行新的攻击的可能性，这种神经系统疾病每 10,000-15,000 名女孩中就有一人罹患这种疾病。公共卫生启示 这项资助首次确定了神经胶质细胞分泌的因子作为雷特综合征神经元损伤的根本原因的潜在作用。如果正如我们的数据所表明的那样，神经胶质效应是由于抑制性生长因子的分泌引起的，那么这就增加了对 RTT 患者进行治疗干预的可能性。

项目成果

Non-cell autonomous influence of MeCP2-deficient glia on neuronal dendritic morphology.

MeCP2 缺陷胶质细胞对神经元树突形态的非细胞自主影响。

• 发表时间: 2009-03
• 影响因子: 25
• 作者: Ballas, Nurit;Lioy, Daniel T;Grunseich, Christopher;Mandel, Gail
• 通讯作者: Mandel, Gail

Neuronal activity induces glutathione metabolism gene expression in astrocytes.

神经元活动诱导星形胶质细胞中谷胱甘肽代谢基因的表达。

• 发表时间: 2018
• 影响因子: 6.2
• 作者: McGann, James C;Mandel, Gail
• 通讯作者: Mandel, Gail

Effect of Sarizotan, a 5-HT1a and D2-like receptor agonist, on respiration in three mouse models of Rett syndrome.

Sarizotan（一种 5-HT1a 和 D2 样受体激动剂）对三种 Rett 综合征小鼠模型呼吸的影响。

• 发表时间: 2014-06
• 影响因子: 6.4
• 作者: Abdala, Ana P;Lioy, Daniel T;Garg, Saurabh K;Knopp, Sharon J;Paton, Julian F R;Bissonnette, John M
• 通讯作者: Bissonnette, John M

Astrocytes conspire with neurons during progression of neurological disease.

在神经系统疾病的进展过程中，星形胶质细胞与神经元协同作用。

• 发表时间: 2012-10
• 影响因子: 5.7
• 作者: McGann, James C;Lioy, Daniel T;Mandel, Gail
• 通讯作者: Mandel, Gail

MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain.

MeCP2 对于在出生后大脑发育的后期和成熟的成年大脑中维持成熟的神经元网络和整体大脑解剖结构至关重要。

• 发表时间: 2012-07-18
• 作者: Nguyen, Minh Vu Chuong;Du, Fang;Felice, Christy A;Shan, Xiwei;Nigam, Aparna;Mandel, Gail;Robinson, John K;Ballas, Nurit
• 通讯作者: Ballas, Nurit