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.

项目概要/摘要 额颞叶痴呆 (FTD) 是一种致命的神经退行性疾病，与精神紊乱有关 在许多基因中。 FTD 属于一组被归类为阿尔茨海默病相关痴呆的痴呆症 （ADRD）。 9 号染色体开放阅读框 72 (C9orf72) 中的六核苷酸重复扩增最为频繁 与 FTD 相关的常见基因改变。然而，将 C9orf72 扩展与 神经毒性仍未完全表征。 组蛋白是染色质的蛋白质支架。它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相互作用的模型 修改，这一概念在 FTD 中并未得到很好的描述。我们提出的总体假设是 蛋白质聚集的毒性作用与组蛋白标记的改变和基因表达的改变有关。我们揭示了一个 由 Aurora B 介导的全基因组组蛋白 H3 丝氨酸 10 (H3S10ph) 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 导致细胞核中 Aurora B 激酶活性增加，进而导致 H3S10ph 增加 导致基因表达异常和细胞死亡。使用 C9orf72 和 C9orf72 的酵母过表达模型 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 增加影响的地区。 总体而言，该研究计划将揭示 FTD 中发挥作用的新表观遗传机制，同时维持 我们的向上研究轨迹和丰富布鲁克林本科生的研究环境 大学。这项研究的长期好处是创建一个新颖的机制框架，可以带来新的、 治疗 FTD 和其他 ADRD 的替代方法。