Astrocyte regulation of cortical neurodegeneration in C9orf72 FTD/ALS

项目摘要 基因C9 orf 72的第一内含子中的GGGGCC（G4 C2）六核苷酸重复扩增（HRE）是 与额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）相关的最常见的遗传异常 硬化症（ALS）。该病的发病机制最终导致皮质前脑的并发变性 和脊髓运动神经元，并导致运动功能和痴呆的临床缺陷。虽然C9 orf 72- FTD/ALS疾病的发病机制已在脊髓运动神经元中得到充分表征， 虽然观察到的神经变性归因于脊髓星形胶质细胞，但关于神经变性的机制知之甚少。 皮质星形胶质细胞的病理生物学及其在皮质神经退行性变中的作用， 与痴呆症症状的关系在这项补助的父母补助金中，我们假设 皮质星形胶质细胞在非细胞自主性疾病病理学中起着不可或缺的作用， C9 orf 72-FTD/ALS中皮质神经元的变性。为了验证这一假设，我们提出了细胞 以及死后前脑尸检组织和患者来源的iPSC皮质神经元的分子分析， 皮质星形胶质细胞共培养系统。通过这一补充，我们扩大了这些研究，并建议 研究星形胶质细胞-神经元接触依赖机制（Aim 1）和星形胶质细胞分泌的 皮质神经退行性变的因素（目的2）。这些贡献将使用iPSC皮质星形胶质细胞进行测试- 皮层神经元共培养模型。分配到这个项目的研究生Lynette Buffett女士将专注于 对已知的星形胶质细胞蛋白（例如，神经配蛋白和肝配蛋白），与神经元突触直接接触， 蛋白质，以及涉及突触结构和功能的星形胶质细胞分泌蛋白质（例如Hevin，P.A.， 血小板反应蛋白、磷脂酰肌醇蛋白）。勒奈特将彻底研究这些蛋白质在退化中的作用， 皮质神经元这些分析将与在父母补助金下进行的研究一起， 时间阐明皮质星形胶质细胞在C9 orf 72 - 2中皮质神经元神经变性中的作用。 FTD/ALS，解决痴呆症在这一谱系障碍的疾病机制。此外，这项工作将 为药物靶点鉴定提供了新的机会，希望能为药物靶点鉴定新的治疗方法。 影响患者人群。

PROJECT ABSTRACT The GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the gene C9orf72, is the most common genetic abnormality associated with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The disease pathogenesis ultimately leads to the concurrent degeneration of cortical forebrain and spinal motor neurons, and result in the clinical deficits of motor function and dementia. While the C9orf72- FTD/ALS disease pathogenesis has been well characterized in spinal motor neurons and a contribution of the observed neurodegeneration has been attributed to spinal cord astrocytes, there is little known about the pathobiology in cortical astrocytes and their role in cortical neurodegeneration, which is proposed to contribute to the dementia symptoms in this patient population. In the parent grant of this supplement, we hypothesized that cortical astrocytes play an integral role in the non-cell autonomous disease pathology contributing to the degeneration of cortical neurons in C9orf72-FTD/ALS. To test this hypothesis, we proposed cellular and molecular analyses of postmortem forebrain autopsy tissues and patient-derived iPSC cortical neurons and cortical astrocytes co-culture systems. With this supplement, we expand on these studies and propose to examine the contribution of astrocyte-neuron contact-dependent mechanisms (Aim 1) and astrocyte-secreted factors (Aim 2) in cortical neurodegeneration. These contributions will be tested using iPSC cortical astrocyte- cortical neuron co-culture models. The graduate student assigned to this project, Ms. Lynette Bustos, will focus on known astrocyte proteins (e.g., neuroligins and ephrins) that make direct contact with neuronal synaptic proteins, as well as astrocyte secreted proteins implicated in synapse structure and function (e.g. Hevin, SPARC, thrombospondins, glypicans). Lynette will thoroughly examine the role of these proteins in the degeneration of cortical neurons. Together with the studies performed under the parent grant, these analyses will for the first time elucidate the contributing role of cortical astrocytes in the neurodegeneration of cortical neurons in C9orf72- FTD/ALS, addressing the disease mechanisms of dementia in this spectrum disorder. Additionally, this work will provide novel opportunities for drug target identification with the hope of identifying novel therapeutics for the affected patient populations.