RNA metabolism in pathology of AOA2/ALS4 neurodegenerative disorders

所有生物体都以基因的形式包含遗传信息，这些基因编码蛋白质——生命的关键组成部分。在基因表达的过程中，编码在DNA序列中的信息被转移到信使RNA（转录）中，然后去除非编码的中间序列（剪接），并将该分子解码为蛋白质（翻译）。每个基因表达步骤都受到多个调控事件的影响，以确保最终的蛋白质产物是正确的。现在很清楚，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2型共济失调动眼肌失用症（AOA2）和4型肌萎缩性侧索硬化症（ALS4）的病理机制，这两种高度致残的遗传性疾病，以脑和脊髓变性为特征，导致进行性肌肉无力并最终萎缩。在这些疾病中发生突变的基因编码了一种叫做senataxin的蛋白质。自2004年发现AOA2/ALS4突变以来，在表征senataxin蛋白的功能或AOA2/ALS4病理的分子机制方面进展甚微。为了研究senataxin蛋白在人类细胞中的功能，我们将结合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体细胞中进行实验。我们假设AOA2/ALS4病理是由于在转录过程中出现的与解决RNA和DNA之间连接相关的senataxin功能缺陷引起的。如果RNA/DNA分子没有被正确地分解，它们的积累可能对细胞有害，导致病理。首先，我们将利用现代技术分析全细胞基因组，描述在senataxin突变的细胞中观察到的转录和RNA加工缺陷。我们还将确定AOA2/ALS4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。我们还将发现新的senataxin相互作用伙伴，并研究它们对基因表达过程和AOA2/ALS4病理的贡献。我们的项目重点研究senataxin的功能，为AOA2/ALS4疾病的病理提供分子线索。越来越明显的是，RNA加工可能代表了许多神经退行性疾病的共同致病机制。约50%的特征性人类遗传疾病与转录/RNA加工不当有关。这强调了我们研究的基础分子生物学方法对理解AOA2/ALS4病理的重要性。因此，开发新的基于RNA的治疗方法，改善AOA2/ALS4等存在RNA加工缺陷的神经退行性患者的健康和生活质量，是我们研究的一个可能的前景。

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.