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: 10359300
• 负责人: Mariana Plazas Torrente
• 金额: $ 47.1万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359300
• 关键词: Address; Affect; Age; Alzheimer' s disease related dementia; Amyotrophic Lateral Sclerosis; Animals; Brain; C9ORF72; Cell Death; Cell Nucleus; Cell Survival; Cells; ChIP-seq; Chromatin; DNA; Data; Degenerative Disorder; Dementia; Dipeptides; Disease; Disease Progression; Disease model; Environment; Epigenetic Process; Frontotemporal Dementia; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genomic Segment; Genomics; Goals; Histone H3; Histones; Human; Immunofluorescence Immunologic; Induced pluripotent stem cell derived neurons; Investigation; Lead; Link; Mass Spectrum Analysis; Mediating; Messenger RNA; Modeling; Modification; Molecular; Motor Neurons; Movement; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Pathway Analysis; Pathway interactions; Patients; Persons; Pharmacology; Phosphorylation; Phosphotransferases; Play; Post-Translational Protein Processing; Process; Prognosis; Proteins; Proteomics; Research; Role; Sampling; Scaffolding Protein; Serine; Temporal Lobe; Testing; Tissue Model; Toxic effect; Yeast Model System; Yeasts; aurora B kinase; base; college; epigenome; frontal lobe; frontotemporal lobar dementia-amyotrophic lateral sclerosis; fused in sarcoma; genome-wide; graduate student; histone modification; improved outcome; induced pluripotent stem cell; inhibitor; interest; mutant; neuroprotection; neurotoxicity; novel; nucleocytoplasmic transport; overexpression; prevent; protein TDP-43; protein aggregation; sex; undergraduate student

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.

额颞叶痴呆（FTD）是一种致命的神经退行性疾病， 在许多基因中。FTD属于一组痴呆，归类为阿尔茨海默病相关痴呆 （ADRD）.在9号染色体开放阅读框72（C9 orf 72）中的六核苷酸重复扩增最多 与FTD相关的常见遗传改变。然而，将C9 orf 72扩展与 神经毒性的特征仍不完全。 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之间相互作用的模型 修饰，这是一个在FTD中没有很好描述的概念。我们提出了一个总体假设， 蛋白质聚集的毒性作用与改变的组蛋白标记和改变的基因表达有关。我们揭示了 Aurora B介导的组蛋白H3丝氨酸10（H3 S10 ph）磷酸化的全基因组增加 激酶，作为与C9 orf 72扩增相关的重要修饰。我们认为C9 orf 72突变 导致细胞核中极光B激酶活性增加，进而导致H3 S10 ph增加 导致异常基因表达和细胞死亡。使用C9 orf 72和C9 orf 74的酵母过表达模型， 人类神经元模型的具体目标是：（1）表征H3 S10 ph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;和（3）定义基因组 受H3 S10 ph影响的区域增加。 总的来说，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研究环境，为本科生在布鲁克林 学院这项研究的长期利益是创造一个新的机制框架， 治疗FTD和其他ADRD的替代方法。