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RNA metabolism in pathology of AOA2/ALS4 neurodegenerative disorders

AOA2/ALS4 神经退行性疾病病理学中的 RNA 代谢

基本信息

批准号：
MR/J007870/1
负责人：
Natalia Gromak
金额：
$ 55.69万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FJ007870%2F1
关键词：
RNA metabolism pathology AOA2 ALS4

项目摘要

All living organisms contain genetic information in a form of genes, which code for proteins - key building blocks of life. During the process of gene expression information from the gene, encoded in a DNA sequence is transferred into messenger RNA (transcription) followed by removal of non-coding intervening sequences (splicing), and decoding of this molecule into protein (translation). Each gene expression step is subjected to multiple regulatory events ensuring that the final protein product is correct. Now it became clear that key regulatory elements in gene expression are represented by the RNA. In this research project we will investigate the mechanism underlying the pathology of ataxia oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis type 4 (ALS4), highly disabling inherited disorders, characterized by degeneration in the brain and spinal cord, causing progressive muscle weakness and finally atrophy. The gene mutated in these diseases encodes a protein called senataxin. Since the discovery of AOA2/ALS4 mutations in 2004, little progress has been made to characterize the function of senataxin protein or molecular mechanisms of AOA2/ALS4 pathology.To study the function of senataxin protein in human cells, we will combine our expertise in RNA field with cutting edge high throughput technology in gene expression. In particular, we will perform experiments in human cells, which lack senataxin or were derived from patients' tissues. We hypothesise that AOA2/ALS4 pathologies arise due to defects in senataxin function associated with resolving connections between RNA and DNA, appearing during the process of transcription. If RNA/DNA molecules are not resolved properly, their accumulation can be detrimental to the cells causing pathologies. Initially, we will characterise the defects in transcription and RNA processing observed in cells with senataxin mutations using modern technologies analysing whole cell genome. We will also determine if RNA/DNA profile is perturbed in AOA2/ALS4 patients, and how it contributes to neurodegeneration. Furthermore, we will investigate the role of senataxin in transcription and RNA splicing. We will also identify new senataxin-interacting partners and study their contribution towards gene expression process and AOA2/ALS4 pathology.Our project focuses on the function of senataxin, providing molecular clues for the pathology of AOA2/ALS4 diseases. It's becoming apparent that RNA processing may represent a common pathogenic mechanism involved in many neurodegenerative disorders. Around 50% of all characterised human genetic diseases are associated with inappropriate transcription/RNA processing. This emphasises the importance of fundamental molecular biology approach of our research towards understanding AOA2/ALS4 pathology. Therefore, the development of novel RNA-based therapies, improving the health and quality of life of AOA2/ALS4 and other neurodegenerative patients with defects of RNA processing, is a likely prospect of our research.

所有生物体都以基因的形式包含遗传信息，基因编码蛋白质-生命的关键组成部分。在基因表达的过程中，来自基因的信息，编码在DNA序列中的被转移到信使RNA中（转录），然后去除非编码间插序列（剪接），并将此分子解码成蛋白质（翻译）。每个基因表达步骤都经历多个调控事件，以确保最终蛋白质产物是正确的。现在已经很清楚，基因表达中的关键调控元件是由RNA代表的。在本研究项目中，我们将研究共济失调性眼用不能2型（AOA 2）和肌萎缩性侧索硬化4型（ALS 4）的病理机制，高度致残的遗传性疾病，其特征是大脑和脊髓变性，导致进行性肌无力，最终萎缩。在这些疾病中突变的基因编码一种称为senataxin的蛋白质。自2004年发现AOA 2/ALS 4突变以来，senataxin蛋白的功能和AOA 2/ALS 4病理的分子机制的研究进展甚微。为了研究senataxin蛋白在人类细胞中的功能，我们将联合收割机结合我们在RNA领域的专业知识和尖端的高通量基因表达技术。特别是，我们将在缺乏senataxin或来自患者组织的人类细胞中进行实验。我们假设AOA 2/ALS 4病理是由于在转录过程中出现的与解决RNA和DNA之间的连接相关的senataxin功能缺陷引起的。如果RNA/DNA分子没有被正确地分解，它们的积累可能对引起病理的细胞有害。最初，我们将使用现代技术分析整个细胞基因组，以证实在senataxin突变细胞中观察到的转录和RNA加工缺陷。我们还将确定AOA 2/ALS 4患者的RNA/DNA谱是否受到干扰，以及它如何导致神经退行性变。此外，我们将研究senataxin在转录和RNA剪接中的作用。我们还将鉴定新的senataxin相互作用伙伴，并研究它们对基因表达过程和AOA 2/ALS 4病理学的贡献。我们的项目重点关注senataxin的功能，为AOA 2/ALS 4疾病的病理学提供分子线索。越来越明显的是，RNA加工可能代表了许多神经退行性疾病中涉及的常见致病机制。大约50%的人类遗传疾病与不适当的转录/RNA加工有关。这强调了我们研究的基础分子生物学方法对理解AOA 2/ALS 4病理学的重要性。因此，开发新的基于RNA的治疗方法，改善AOA 2/ALS 4和其他RNA加工缺陷的神经退行性疾病患者的健康和生活质量，是我们研究的一个可能的前景。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Out of balance: R-loops in human disease.

DOI：
10.1371/journal.pgen.1004630
发表时间：
2014-09
期刊：
PLoS genetics
影响因子：
4.5
作者：
Groh M;Gromak N
通讯作者：
Gromak N

Dual Processing of R-Loops and Topoisomerase I Induces Transcription-Dependent DNA Double-Strand Breaks.

DOI：
10.1016/j.celrep.2019.08.041
发表时间：
2019-09-17
期刊：
Cell reports
影响因子：
8.8
作者：
Cristini A;Ricci G;Britton S;Salimbeni S;Huang SN;Marinello J;Calsou P;Pommier Y;Favre G;Capranico G;Gromak N;Sordet O
通讯作者：
Sordet O

RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage.