New Targets in C9orf72 FTD: Exploring Histone H3 S10 Phosphorylation

额颞叶痴呆(FTD)是一种致命的神经退行性疾病，与神经功能障碍有关 在许多基因中。FTD属于被归类为阿尔茨海默病相关痴呆的一组痴呆 (ADRD)。9号染色体开放阅读框72(C9orf72)的六核苷酸重复序列扩增最多 与FTD相关的常见基因改变。然而，将C9orf72扩展与 神经毒性仍未完全确定。 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 表情。我们的初步数据支持蛋白质聚集和组蛋白相互作用的模型 修改，这一概念在FTD中没有得到很好的描述。我们提出的最重要的假设是 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。我们揭示了一个 Aurora B介导组蛋白H3丝氨酸10(H3S10ph)磷酸化的全基因组增强 作为与C9orf72扩张相关的重要修饰。我们认为C9orf72突变 导致细胞核内Aurora B激酶活性增加，进而导致H3S10ph升高 导致基因表达异常和细胞死亡。使用C9orf72和C9orf72两种酵母过表达模型 人类神经元模型这项提议的具体目标是：(1)表征H3S10ph之间的串扰 和其他组蛋白修饰；(2)测试极光B激酶在细胞死亡中的作用；以及(3)定义基因组 受H3S10ph影响的地区增加。 总体而言，这项研究计划将揭示在FTD中发挥作用的新的表观遗传机制，同时保持 我们向上的研究轨迹和丰富的布鲁克林本科生的研究环境 上大学。这项研究的长期好处是创建一种新的机制框架，可以导致新的、 治疗FTD和其他ADRDS的替代方法。

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.