New Targets in C9orf72 FTD: Exploring Histone H3 S10 Phosphorylation

C9orf72 FTD 的新靶点：探索组蛋白 H3 S10 磷酸化

• 批准号: 10786872
• 负责人: Mariana Plazas Torrente
• 金额: $ 10.44万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10786872
• 关键词: Alzheimer' s disease related dementia; C9ORF72; Cell Death; Cell Nucleus; Chromatin; DNA Packaging; Data; Dementia; Disease; Environment; Epigenetic Process; Frontotemporal Dementia; Gene Expression; Genes; Genomic Segment; Goals; Histone H3; Histones; Human; Lead; Link; Mediating; Modeling; Modification; Mutation; Neurodegenerative Disorders; Neurons; Phosphorylation; Play; Post-Translational Protein Processing; Proteins; Research; Role; Scaffolding Protein; Serine; Testing; Toxic effect; Yeasts; aurora B kinase; college; genome-wide; histone modification; neurotoxicity; novel; overexpression; protein aggregation; undergraduate student

PROJECT SUMMARY/ABSTRACT Frontotemporal dementia (FTD) is a fatal neurodegenerative disease that has been linked to disruptions in many genes. FTD belongs to a group of dementias catalogued as Alzheimer's Disease Related Dementias (ADRD). Hexanucleotide repeat expansions in Chromosome 9 Open Reading Frame 72 (C9orf72) are the most common genetic alteration linked to FTD. However, the precise mechanisms linking C9orf72 expansions to neurotoxicity remain incompletely characterized. Histones are the protein scaffold of chromatin. Their post-translational modification can alter gene expression. Our preliminary data support a model of interplay between protein aggregation and histone modifications, a notion that is not well characterized in FTD. We propose the overarching hypothesis that the toxic effect of protein aggregation is related to altered histone marks and altered gene expression. We reveal a genome-wide increase in the phosphorylation of Histone H3 on Serine 10 (H3S10ph), mediated by Aurora B kinase, as an important modification associated with C9orf72 expansions. We propose that C9orf72 mutations lead to increased activity Aurora B kinase in the nucleus which in turn leads to H3S10ph increases causing aberrant gene expression and cell death. Using both yeast overexpression models of C9orf72 and human neuronal models the specific goals of this proposal are to: (1) characterize crosstalk between H3S10ph and other histone modifications; (2) test the role of Aurora B Kinase in cell death; and (3) define the genomic regions impacted by H3S10ph increases. Overall, this research plan will uncover novel epigenetic mechanisms at play in FTD while maintaining our upward research trajectory and enriching the research environment for undergraduate students at Brooklyn College. The long-term benefit of this research is to create a novel mechanistic framework that can lead to new, alternative approaches in the treatment of FTD and other ADRDs.

项目摘要/摘要 额颞痴呆（FTD）是一种致命的神经退行性疾病，与中断有关 在许多基因中。 FTD属于一组痴呆症，分类为阿尔茨海默氏病有关的痴呆症 （ADRD）。六核苷酸在9号染色体开放式阅读框72（C9orf72）中的重复膨胀最多。 与FTD有关的常见遗传改变。但是，将C9orf72扩展与 神经毒性仍然不完全表征。 组蛋白是染色质的蛋白质支架。他们的翻译后修饰可以改变基因 表达。我们的初步数据支持蛋白质聚集和组蛋白之间的相互作用模型 修改，在FTD中未充分表征的概念。我们提出了一个总体假设 蛋白质聚集的毒性作用与组蛋白标记改变和基因表达改变有关。我们揭示一个 由Aurora B介导的丝氨酸10（H3S10PH）上组蛋白H3磷酸化的全基因组磷酸化增加 激酶，作为与C9ORF72扩展相关的重要修饰。我们建议C9orf72突变 导致活性增加的核中Aurora B激酶，进而导致H3S10PH的增加 引起异常的基因表达和细胞死亡。使用C9orf72和 人类神经元模型该提案的具体目标是：（1）表征H3S10PH之间的串扰 和其他组蛋白修饰； （2）测试Aurora B激酶在细胞死亡中的作用； （3）定义基因组 受H3S10PH影响的地区增加。 总体而言，该研究计划将在FTD中发现新颖的表观遗传机制，同时保持 我们向上的研究轨迹并丰富了布鲁克林大学生的研究环境 大学。这项研究的长期好处是创建一个新型的机械框架，可以导致新的机械框架 FTD和其他ADRD的治疗方法的替代方法。