Examining the coupling of small GTPase activation and metabolism of the phosphoinositide lipid PI(3,5)P2 in Charcot Marie Tooth Type 4 Neuropathies

Charcot-Marie Tooth 4型（CMT 4）神经病是一组以髓磷脂失效为特征的疾病，髓磷脂是向体内肌肉发送信号的神经的“绝缘”。患有CMT 4的患者通常在生命早期发展，这意味着他们一生都需要在行动和基本任务方面获得帮助。这是一种进行性疾病，髓鞘绝缘慢慢停止正确包裹在神经周围，这是为了绝缘。这会阻止神经正确地向肢体发送信号，导致感觉和运动障碍（特别是在较远的肢体）。随着时间的推移，这种疾病会慢慢恶化，如果我们了解问题所在，疾病过程可能会被适当的治疗所阻止，甚至逆转。我们希望研究几个导致CMT 4的相关基因。它们具有不同的功能，但共同作用将蛋白质移到细胞表面或从细胞表面移出（我们称之为运输）。CMT 4病理的发生是因为制造髓鞘的细胞中的适当运输失败，这意味着应该在制造髓鞘的细胞表面的蛋白质没有正确或在错误的时间到达。其中5个基因（我们想要研究的基因）制造酶。这些酶中的3种（称为Frabin、MTMR 13和MTMR 5）开启GTP酶。4种酶（称为MTMR 2，MTMR 13，MTMR 5和图4）作用于一种罕见的脂质（PI（3，5）P2），通过添加一个“标签”来帮助细胞进行运输，该标签告诉您在运输过程中您在细胞内的位置。小GTP酶是另一种“标签”-当它们被打开时，它们指示某些蛋白质组聚集在膜上。PI（3，5）P2等脂质和小GTPases等蛋白质可以共同指定将蛋白质移动到细胞表面的过程的时间和地点。对于CMT 4患者，我们仍然不知道PI（3，5）P2脂质的重要池在细胞中的位置，以及在这些基因突变的CMT 4患者中，应该由小GTP酶协调的行动未能发生。上述酶是最有希望的治疗靶点，因为它们可能是可药用的，或者可以用其他方法代替它们的酶活性。该项目旨在了解制造髓鞘的细胞中出现了什么问题，并确定最佳治疗靶点，为治疗策略的研究奠定基础。

Charcot-Marie Tooth type 4 (CMT4) neuropathies are a group of diseases characterized by a failure of myelin, the "insulation" for the nerves sending signals to muscles in the body. Patients who have CMT4 generally develop it early in life, meaning that they face a lifetime of needing assistance with mobility and basic tasks. It is a progressive disorder, where the myelin insulation slowly stops wrapping properly around the nerves it is meant to insulate. This stops the nerve from sending signals properly to the limbs, leading to both sensory and motor impairment (particularly in the more distant limbs). As this disease slowly gets worse over time, there is a possibility that if we understand what is going wrong, the disease process could be arrested or even reversed by the appropriate therapy.We wish to study several related genes which all cause CMT4. These have different functions, but work together to move proteins to and from the surface of the cell (we call this trafficking). CMT4 pathologies occur because of the failure of proper trafficking in the cells that make myelin, meaning proteins that should be at the surface of the myelin-making cells don't arrive properly or at the wrong time.CMT4 pathologies are caused by mutation any of 11 different genes. 5 of these genes (the ones we want to study) make enzymes. 3 of these enzymes (called Frabin, MTMR13, and MTMR5) switch on GTPases. 4 enzymes (called MTMR2, MTMR13, MTMR5 and Fig4) act on a rare lipid (PI(3,5)P2) which helps conduct trafficking in the cell by adding a 'tag' which tells you where inside the cell you are during the trafficking process. Small GTPases are another kind of 'tag'- when they are switched on, they instruct certain groups of proteins to collect on the membrane. Together, lipids like PI(3,5)P2 and proteins like small GTPases can specify a time and a place for the process of moving proteins to the cell surface. For CMT4 patients we still don't know where the important pool of PI(3,5)P2 lipid is in the cell, and what actions that should be co-ordinated by small GTPases are failing to happen in CMT4 patients with mutations in these genes. The enzymes mentioned above are the most promising targets for therapies, as they are potentially druggable, or can have their enzymatic activities replaced by other means. This project aims to understand what is going wrong in the cells making myelin and identify the best targets for therapy, preliminary to studies for therapeutic strategies.