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

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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.