Targeting axonal transport regulation by neurotrophic factors to treat peripheral nerve degeneration

通过神经营养因子调节轴突运输来治疗周围神经变性

• 批准号: MR/Y010949/1
• 负责人: James Sleigh
• 金额: $ 340.05万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY010949%2F1
• 关键词: Targeting; axonal; transport; regulation; neurotrophic

Charcot-Marie-Tooth disease (CMT) is an inherited nervous system disease that affects 1 in about 2,500 people, which makes it one of the most common diseases to affect both nerves and muscles. The symptoms of CMT usually begin during teenage years, but the disease does not affect survival, therefore it causes life-long disability, for which the estimated societal cost is approximately £0.5 billion per year in the UK alone. People with CMT have mobility issues and difficulties with sensation, because two different types of nerve cell, known as motor neurons and sensory neurons, malfunction and progressively deteriorate. It is unknown why these peripheral nerves are affected, which has made it difficult to develop treatments for CMT.Mutations in more than 100 different genes cause CMT, and the collection of genes linked to the most CMT subtypes all produce enzymes known as aminoacyl tRNA-synthetases (ARSs). The ARS enzymes are essential to all cells for making protein. To better understand how CMT is caused, we study two ARS genes - GARS1, which produces GlyRS protein and is linked to CMT type 2D (CMT2D) and YARS1, which produces TyrRS protein and is linked to a subtype known as DI-CMTC. Using cell and mouse models, we study CMT2D and DI-CMTC to understand why motor and sensory neurons deteriorate, because this will enable us to design better treatments to combat the disease.CMT-causing mutations in GARS1 and YARS1 affect the structure of the proteins they produce. My laboratory discovered that this causes mutant GlyRS and mutant TyrRS to mis-interact with a series of important proteins called Trk receptors, which are found on the surface of nerve cells and normally bind to survival molecules called neurotrophins.Recently, we have shown that the aberrant association between mutant ARS proteins and Trk receptors impairs a critical and continually active process in nerve cells known as axonal transport. Nerve cells have a long, thin pipe-like structure called an axon, which helps to deliver electrical signals and cellular components over large distances. For nerves to function correctly and survive, they require many substances to be delivered up and down axons by the process of axonal transport. In particular, motor and sensory neurons rely on this process to deliver neurotrophins from muscles towards the brain. We therefore boosted the levels of one of these key neurotrophins, BDNF, in muscles of CMT mice and showed that it can treat the disruption in axonal transport and improve other features of the disease. We now propose to examine in detail the role that neurotrophins and other similar neurotrophic factors (NTFs) play in regulating the process of axonal transport in motor and sensory nerves. Doing so, will not only allow us to better understand why these peripheral nerves deteriorate in CMT, but it will enable us to achieve our main goal, which is to develop a multi-pronged approach to treat the symptoms of CMT and improve patient quality of life.We will accomplish this through four main objectives:1) We will assess the structures of ARS and Trk receptor proteins, identifying exactly how they mis-interact, so that we can design treatments blocking specifically these aberrant associations.2) To identify key proteins other than NTFs that can be targeted to treat defects in axonal transport, we will generate and study new models of CMT2D and DI-CMTC using human motor neurons.3) By testing a collection of NTFs, we will identify whether molecules other than BDNF can be supplied to muscle to alleviate the axonal transport impairment in both human neurons and mice.4) We will adapt our treatment strategy to enable the continual and long-term delivery of BDNF, and other NTFs identified in Aim 3, to all muscles using harmless viruses and then test the effectiveness of these therapies in mouse models of several different subtypes of CMT.

腓骨肌萎缩症 (CMT) 是一种遗传性神经系统疾病，约 2,500 人中就有一人受影响，这使其成为影响神经和肌肉的最常见疾病之一。CMT 的症状通常在青少年时期开始出现。该疾病不会影响生存，因此会导致终身残疾，仅在英国，每年的社会成本估计就约为 5 亿英镑。患有 CMT 的人会出现行动问题和感觉困难，因为有两种不同类型的神经。被称为运动神经元和感觉神经元的细胞出现功能障碍并逐渐恶化，目前尚不清楚这些周围神经受到影响的原因，这使得开发 CMT 治疗方法变得困难。超过 100 种不同基因的突变会导致 CMT。与大多数 CMT 亚型相关的基因都会产生称为氨酰 tRNA 合成酶 (ARS) 的酶，ARS 酶对于所有细胞制造蛋白质至关重要。研究两个 ARS 基因 - GARS1（产生 GlyRS 蛋白并与 2D 型 CMT (CMT2D) 相关）和 YARS1（产生 TyrRS 蛋白并与 DI-CMTC 亚型相关）。我们利用细胞和小鼠模型研究了 CMT2D 和 YARS1。 DI-CMTC 了解运动和感觉神经元为何恶化，因为这将使我们能够设计出更好的治疗方法来对抗这种疾病。导致 CMT 的 GARS1 和 YARS1 突变会影响我的实验室发现，这会导致突变型 GlyRS 和突变型 TyrRS 与一系列称为 Trk 受体的重要蛋白质发生错误相互作用，这些受体存在于神经细胞表面，通常与称为神经营养素的生存分子结合。最近，我们发现突变 ARS 蛋白和 Trk 受体之间的异常关联会损害神经细胞中称为轴突运输的关键且持续活跃的过程。神经细胞具有一种称为轴突的长而细的管状结构。这有助于长距离传递电信号和细胞成分，为了使神经正常发挥作用并生存，它们需要通过轴突运输过程向上和向下传递许多物质，特别是运动和感觉神经元依赖于这一过程。因此，我们提高了 CMT 小鼠肌肉中其中一种关键神经营养因子 BDNF 的水平，并表明它可以治疗轴突运输的破坏并改善该疾病的其他特征。检查详细介绍神经营养因子和其他类似的神经营养因子 (NTF) 在调节运动和感觉神经轴突运输过程中的作用，这样做不仅可以让我们更好地理解为什么这些周围神经在 CMT 中恶化。使我们能够实现我们的主要目标，即开发一种多管齐下的方法来治疗 CMT 症状并改善患者的生活质量。我们将通过四个主要目标来实现这一目标：1) 我们将评估 ARS 和 Trk 的结构受体识别蛋白质，准确地了解它们如何相互作用，以便我们可以设计专门阻断这些异常关联的治疗方法。2）为了识别除 NTF 之外可用于治疗轴突运输缺陷的关键蛋白质，我们将生成并研究新的模型使用人类运动神经元的 CMT2D 和 DI-CMTC。3) 通过测试一组 NTF，我们将确定除 BDNF 之外的分子是否可以提供给肌肉，以减轻人类神经元和小鼠的轴突运输损伤。4) 我们将适应我们的治疗策略是使用无害的病毒将 BDNF 和目标 3 中确定的其他 NTF 持续长期递送至所有肌肉，然后在几种不同 CMT 亚型的小鼠模型中测试这些疗法的有效性。