Charcot-Marie-Tooth type 2B: Role of the Rab7 GTPase and of Rab7 interacting proteins

Charcot-Marie-Tooth type 2B disease is a peripheral neuropathy characterized by loss of sensation at extremities and slowly progressive weakness and wasting of distal muscles. Symptoms usually begin in feet and legs, and only later on reach hands and arms. There is currently no treatment available to cure this disease. Foot ulcers and recurrent infections, which often lead to amputations of the toes, further characterize the type 2B form of the disease, also called ulcero-mutilating. This form is caused by mutations in the rab7 gene. Rab7 is a protein important for the correct form and functioning of lysosomes, the digestive system of all cells, and thus it is not yet clear why alterations of this protein cause problems only to nervous cells of the peripheral nervous system. This project is the result of the collaborative effort of three scientific groups with different expertise and proposes to study the molecular and cellular mechanisms underlying this disease, a necessary step to identify possible treatments in the future. In particular, we propose to study the effects of the mutations of the Rab7 protein on the morphology and function of lysosomes, the digestive system of the cell, and on the degeneration and regeneration processes of the axon, a part of the nervous cell fundamental to conduct nerve impulses. To do that we will use stem cells derived from the skin of the patients in order to produce peripheral nervous cells. This will allow us to perform experiments on patient-derived cells displaying the defect. The discovery of the molecular and cellular mechanisms underlying this disease will allow the identification of targets for designing future effective therapeutical strategies. Furthermore, full understanding of these mechanisms could give new insights for other forms of Charcot-Marie-Tooth due to similar alterations.