Astrocyte regulation of cortical neurodegeneration in C9orf72 FTD/ALS

星形胶质细胞对 C9orf72 FTD/ALS 皮质神经变性的调节

• 批准号: 10526792
• 负责人: Rita Sattler
• 金额: $ 8.71万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-29 至 2024-03-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10526792
• 关键词: ALS patients; Address; Affect; Amyotrophic Lateral Sclerosis; Astrocytes; Autopsy; C9ORF72; Clinical; Coculture Techniques; Cognitive; Dementia; Disease; Drug Targeting; Ephrins; Frontotemporal Dementia; Genes; Glypican; Introns; Modeling; Molecular Abnormality; Molecular Analysis; Motor; Motor Neurons; Nerve Degeneration; Neurons; Pathogenesis; Pathology; Patients; Play; Prosencephalon; Proteins; Regulation; Research Proposals; Role; Spinal; Spinal Cord; Structure; Symptoms; Synapses; System; Testing; Thrombospondins; Time; Tissues; Work; frontotemporal lobar dementia-amyotrophic lateral sclerosis; graduate student; hevin; induced pluripotent stem cell; motor deficit; novel; novel therapeutics; parent grant; patient population

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.

项目摘要 基因 C9orf72 第一个内含子中的 GGGGCC (G4C2) 六核苷酸重复扩展 (HRE) 是 与额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症相关的最常见遗传异常 硬化症（ALS）。该病发病机制最终导致前脑皮质并发变性 和脊髓运动神经元，并导致运动功能和痴呆的临床缺陷。而 C9orf72- FTD/ALS 疾病的发病机制已在脊髓运动神经元中得到了很好的表征，并且是 观察到的神经退行性变归因于脊髓星形胶质细胞，但人们对它知之甚少 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，建议有助于 该患者群体的痴呆症状。在本补充品的家长资助中，我们假设 皮质星形胶质细胞在非细胞自主疾病病理学中发挥着不可或缺的作用 C9orf72-FTD/ALS 中皮质神经元的退化。为了检验这个假设，我们提出了细胞 对死后前脑尸检组织和患者来源的 iPSC 皮质神经元进行分子分析 皮质星形胶质细胞共培养系统。通过这个补充，我们扩展了这些研究并建议 检查星形胶质细胞-神经元接触依赖性机制（目标 1）和星形胶质细胞分泌的贡献 皮质神经变性的因素（目标 2）。这些贡献将使用 iPSC 皮质星形胶质细胞进行测试 皮质神经元共培养模型。分配到该项目的研究生 Lynette Bustos 女士将重点关注 与神经元突触直接接触的已知星形胶质细胞蛋白（例如神经配蛋白和肝配蛋白） 蛋白，以及与突触结构和功能有关的星形胶质细胞分泌蛋白（例如 Hevin、SPARC、 血小板反应蛋白、磷脂酰肌醇蛋白聚糖）。 Lynette 将彻底检查这些蛋白质在退化中的作用 皮质神经元。与在家长资助下进行的研究一起，这些分析将首次 时间阐明皮质星形胶质细胞在 C9orf72- 皮质神经元神经变性中的贡献作用 FTD/ALS，解决了这种谱系障碍中痴呆症的疾病机制。此外，这项工作将 为药物靶标识别提供新的机会，希望为该疾病确定新的治疗方法 受影响的患者群体。