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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，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。