Consequences of Dynamin 2 PH Domain Dysfunction in Charcot-Marie-Tooth Neuropathy

Dynamin 2 PH 结构域功能障碍对腓骨肌神经病的影响

• 批准号: nhmrc : 372104
• 负责人: Prof Adam Mccluskey
• 金额: $ 44.36万
• 依托单位: Children's Medical Research Institute
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2006
• 资助国家: 澳大利亚
• 起止时间: 2006-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/consequences-dynamin-2-tooth-neuropathy/96245
• 关键词: Consequences; Dynamin; PH; Domain; Dysfunction

Our team has just discovered a new gene mutation that causes Charcot-Marie-Tooth (CMT) disease. CMT is a clinically and genetically diverse family of human peripheral neuropathies. CMT neuropathy is the most common inherited peripheral neuropathy, affecting approximately 1 in 2500. It is the most common human genetic disorder known and is caused by fifty or more genes. CMT is of large economic significance since many of the affected individuals are on lifetime invalid pensions and require continual medical and paramedical support. The new mutation we discovered is in a variant form of CMT and affects the protein dynamin 2, in an important region called the PH domain. The normal function of Dyn2 is to retrieve activated receptors for hormones and growth factors from the membrane of cells (caller receptor mediated endocytosis or RME) and it is also required for other functions like cell proliferation. The PH domain is the part of Dyn2 that allows it to move to the appropriate part of the cell when needed to do its job, but it is not known whether the mutation disrupts this function of Dyn2. Since Dyn2 has multiple cellular functions, it is not understood why it might cause the disease. Our goal is to understand why this mutation causes peripheral nerves to degenerate, by revealing which of dynamin's many functions are primarily affected. We expect to uncover a new concept in how RME links to neuronal degeneration. In previous studies we developed the first drugs that interact with PH domains. We will now fully develop these, and synthesise new drugs that interact with the PH domain, as candidates to effect some repair of the damaged PH domain. A better understanding of Dyn2 and endocytosis is crucial to understanding both CMT and ultimately for developing therapies.

我们的团队刚刚发现了一种新的导致Charcot-Marie-Tooth（CMT）疾病的基因突变。CMT是一个临床和遗传多样的人类周围神经病家族。CMT神经病是最常见的遗传性周围神经病，约1/2500。它是已知的最常见的人类遗传疾病，由50个或更多基因引起。CMT具有很大的经济意义，因为许多受影响的人领取终身残疾养恤金，需要持续的医疗和辅助医疗支助。我们发现的新突变是CMT的一种变体形式，影响蛋白动力蛋白2的一个重要区域，称为PH结构域。Dyn 2的正常功能是从细胞膜中取回激素和生长因子的活化受体（caller receptor mediated endocytosis或RME），它也是其他功能如细胞增殖所必需的。PH结构域是Dyn 2的一部分，允许它在需要时移动到细胞的适当部分来完成其工作，但目前尚不清楚突变是否会破坏Dyn 2的这一功能。由于Dyn 2具有多种细胞功能，因此尚不清楚为什么它可能导致疾病。我们的目标是通过揭示发动蛋白的许多功能中哪些主要受到影响，来了解为什么这种突变会导致外周神经退化。我们期望揭示RME如何与神经元变性联系的新概念。在以前的研究中，我们开发了第一种与PH结构域相互作用的药物。我们现在将充分开发这些药物，并合成与PH结构域相互作用的新药，作为修复受损PH结构域的候选药物。更好地理解Dyn 2和内吞作用对于理解CMT和最终开发治疗至关重要。