The role of axonal mRNA translation in Amyotrophic Lateral Sclerosis (resubmission)

轴突 mRNA 翻译在肌萎缩侧索硬化症中的作用（重新提交）

• 批准号: MR/V003933/1
• 负责人: Alexander Whitworth
• 金额: $ 48.34万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV003933%2F1
• 关键词: role; axonal; mRNA; translation; Amyotrophic

Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by the degeneration of motor neurons leading to paralysis and death usually 2-5 years after onset of symptoms. Currently no cure or disease-modifying therapies exist, partly because we still lack basic understanding of the root-cause of the disease. To devise better therapeutic strategies, we need a greater understanding of the molecular and cellular mechanisms responsible for this selective neuronal degeneration. The vast majority of cases are sporadic while 5-10% are inherited. Studying the gene alterations that cause the disease in a rare few cases gives important clues into the causes. Functional studies of mutations that cause the disease have begun to implicate a number of mechanisms. One key mechanism that is emerging is the dysregulation of RNA biology. Current evidence indicates that multiple aspects of mRNA formation and handling are affected in disease conditions, including expression, maturation, stability, subcellular distribution and translation. The key question now is why disruption of mRNA handling leads specifically to the demise of motor nerves to cause ALS. A unique characteristic of motor nerves is their extraordinary length; many times longer than most other nerve types. In recent years, it has become clear that mRNAs can travel to the nerve extremities where they provide templates for local translation to support essential synaptic functions. Bringing these ideas together, we hypothesise that disruptions to the myriad of normal RNA regulatory processes leads to alterations in the population of mRNAs available for translation in motor nerve termini is an important trigger in how ALS starts. To explore this idea, we will determine which mRNA molecules are underdoing translation in adult motor nerve axons in vivo. We will then seek to understand how this profile changes during ageing and under disease conditions. Importantly, this work will go beyond the in vitro conditions of cultured cells by conducting our analysis in an animal model, Drosophila melanogaster. We will address these fundamental questions using the disease-relevant cell type (motor neurons) in their native environment, in an intact neuromuscular circuit. For time, cost and ethical considerations, invertebrate models provide many advantages yet have proven functional similarities to mammalian motor nerves. Moreover, using a genetically tractable animal model will allow us to define the pathological relevance of the mRNAs that are dysregulated by determining their functional impact on the disease-relevant circuits at an organismal level. This type of discovery research is essential to lay the foundations for a clearer understanding of the disease cause to develop more effective therapies.

肌萎缩侧索硬化症（ALS）是一种由运动神经元变性引起的破坏性疾病，通常在症状发作后2-5年导致瘫痪和死亡。目前还没有治愈或改善疾病的疗法，部分原因是我们仍然缺乏对疾病根源的基本了解。为了设计更好的治疗策略，我们需要更好地了解这种选择性神经元变性的分子和细胞机制。绝大多数病例是散发的，而5-10%是遗传的。研究在极少数情况下导致这种疾病的基因改变，可以为病因提供重要线索。对导致这种疾病的突变的功能研究已经开始涉及许多机制。正在出现的一个关键机制是RNA生物学的失调。目前的证据表明，mRNA形成和处理的多个方面在疾病条件下受到影响，包括表达、成熟、稳定性、亚细胞分布和翻译。现在的关键问题是为什么mRNA处理的中断会特别导致运动神经的死亡，从而导致ALS。运动神经的一个独特的特征是它们的非凡长度;比大多数其他神经类型长许多倍。近年来，人们已经清楚mRNA可以到达神经末端，在那里它们为局部翻译提供模板，以支持必要的突触功能。将这些想法结合在一起，我们假设，对无数正常RNA调控过程的破坏导致运动神经末梢中可用于翻译的mRNA群体的改变是ALS如何开始的重要触发因素。为了探索这个想法，我们将确定哪些mRNA分子在体内成年运动神经轴突中翻译不足。然后，我们将试图了解这种情况在衰老和疾病条件下如何变化。重要的是，这项工作将超越体外培养细胞的条件下进行我们的分析，在动物模型，果蝇。我们将使用疾病相关的细胞类型（运动神经元）在其天然环境中，在一个完整的神经肌肉回路中解决这些基本问题。出于时间、成本和伦理方面的考虑，无脊椎动物模型提供了许多优点，但已证明与哺乳动物运动神经功能相似。此外，使用遗传学上易于处理的动物模型将使我们能够通过确定它们在生物体水平上对疾病相关回路的功能影响来定义失调的mRNA的病理相关性。这种类型的发现研究对于更清楚地了解疾病原因以开发更有效的治疗方法奠定基础至关重要。

项目成果

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction in C9orf72 ALS/FTD in vivo models and patient iNeurons

• DOI: 10.1101/2023.10.02.560439
• 发表时间: 2023-10
• 期刊: bioRxiv
• 作者: Wing Hei Au;Leonor Miller-Fleming;Alvaro Sanchez-Martinez;James A. K. Lee;Madeleine J. Twyning;H. Prag;Sarah Granger;Katie Roome;L. Ferraiuolo;H. Mortiboys;Alexander J. Whitworth