Astrocyte regulation of cortical neurodegeneration in C9orf72 FTD/ALS

项目摘要 C9orf72基因第一内含子的GGGGCC(G4C2)六核苷酸重复序列扩展(HRE)是 与额颞性痴呆(FTD)和肌萎缩侧索硬化症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同时变性。 和脊髓运动神经元，并导致临床运动功能障碍和痴呆。而C9orf72- FTD/ALS疾病的发病机制已被很好地描述在脊髓运动神经元中，并在 观察到的神经退行性变归因于脊髓星形胶质细胞，对此知之甚少 皮质星形胶质细胞的病理生物学及其在皮质神经变性中的作用，这被认为是有贡献的 这些患者群体中的痴呆症症状。在这份补充材料的家长拨款中，我们假设 皮质星形胶质细胞在非细胞自主性疾病病理中起着不可或缺的作用 C9orf72-FTD/ALS大脑皮层神经元变性。为了验证这一假设，我们提出了细胞 对死后前脑尸检组织和患者来源的IPSC皮质神经元和 皮质星形胶质细胞共培养体系。在本补充资料中，我们对这些研究进行了扩展，并建议 研究星形胶质细胞-神经元接触依赖机制(目标1)和星形胶质细胞分泌的作用 皮质神经退行性变的因素(目标2)。这些贡献将使用iPSC皮质星形胶质细胞进行测试。 大脑皮层神经元共培养模型。分配给这个项目的研究生Lynette Bustos女士将专注于 关于已知的与神经元突触直接接触的星形胶质细胞蛋白(如神经连接蛋白和肾上腺素) 蛋白质，以及星形胶质细胞分泌的与突触结构和功能有关的蛋白质(例如，Hevin，SPARC， 凝血酶原蛋白、螺杆菌)。Lynette将彻底研究这些蛋白质在细胞退行性变中的作用 皮质神经元。连同在父母资助下进行的研究，这些分析将是第一次 时间阐明皮质星形胶质细胞在C9orf72-皮质神经元退行性变中的作用 FTD/ALS，解决了这种谱系障碍中痴呆的疾病机制。此外，这项工作将 为药物靶点识别提供新的机会，希望为癌症寻找新的治疗方法 受影响的患者群体。

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.