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.

Charcot-Marie-Tooth病（CMT）是一种遗传性神经系统疾病，约2,500人中有1人患病，这使得它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开始，但这种疾病不影响生存，因此它会导致终身残疾，仅在英国，估计每年的社会成本约为5亿英镑。CMT患者有行动不便和感觉困难，因为两种不同类型的神经细胞，即运动神经元和感觉神经元，发生故障并逐渐恶化。目前尚不清楚为什么这些周围神经受到影响，这使得很难开发CMT的治疗方法。超过100种不同基因的突变导致CMT，与大多数CMT亚型相关的基因集合都产生称为氨酰tRNA合成酶（ARS）的酶。ARS酶是所有细胞制造蛋白质所必需的。为了更好地了解CMT是如何引起的，我们研究了两个ARS基因-GARS 1，它产生GlyRS蛋白并与CMT 2D型（CMT 2D）和YARS 1相关联，它产生TyrRS蛋白并与称为DI-CMTC的亚型相关联。我们使用细胞和小鼠模型研究CMT 2D和DI-CMTC，以了解运动和感觉神经元退化的原因，因为这将使我们能够设计更好的治疗方法来对抗这种疾病。GARS 1和YARS 1中引起CMT的突变会影响它们产生的蛋白质的结构。我的实验室发现，这导致突变的GlyRS和突变的TyrRS与一系列称为Trk受体的重要蛋白质发生错误相互作用，这些蛋白质存在于神经细胞表面，通常与称为神经营养因子的生存分子结合。最近，我们已经证明，突变的ARS蛋白质和Trk受体之间的异常关联损害了神经细胞中称为轴突运输的关键和持续活跃的过程。神经细胞有一个长而细的管状结构，称为轴突，它有助于长距离传递电信号和细胞成分。为了使神经正常工作并存活下来，它们需要通过轴突运输过程将许多物质上下传递到轴突。特别是，运动和感觉神经元依靠这个过程将神经营养因子从肌肉输送到大脑。因此，我们提高了CMT小鼠肌肉中这些关键神经营养因子之一BDNF的水平，并表明它可以治疗轴突运输的中断并改善疾病的其他特征。我们现在建议详细研究神经营养因子和其他类似的神经营养因子（NTFs）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了解为什么这些周围神经在CMT中恶化，而且还可以使我们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的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受体蛋白的结构，准确识别它们如何相互作用，这样我们就可以设计出特异性阻断这些异常关联的治疗方法。2）为了鉴定除NTF以外的可以靶向治疗轴突运输缺陷的关键蛋白质，我们将使用人类运动神经元产生和研究CMT 2D和DI-CMTC的新模型。3）通过测试NTF的集合，我们将确定是否可以向肌肉提供BDNF以外的分子，以减轻人类神经元和小鼠的轴突运输损伤。我们将调整我们的治疗策略，使BDNF和目标3中确定的其他NTFs能够使用无害的病毒持续和长期递送到所有肌肉，然后在几种不同亚型的CMT小鼠模型中测试这些疗法的有效性。