Role of the Rab7 protein in hereditary sensory ulcero−mutilating neuropathies.

This is a national project funded by Telethon-Italy. ABSTRACT The inherited neuropathies of the peripheral nervous system show considerable clinical and genetical heterogeneity. Some forms, the ulcero−mutilating neuropathies, are characterized by prominent sensory loss, often complicated by severe infections, arthropathy and amputations. Hereditary sensory neuropathy type IIB (also called Charcot−Marie Tooth type 2B) is clinically characterized by marked distal muscle weakness and wasting, and a high frequency of foot ulcers, infections, and amputations of the toes because of recurrent infections. Recently, three missense mutations in the small GTPase late endosomal protein Rab7 have been identified in autosomal dominant ulcero−mutilating neuropathy families. Rab7 controls late endocytic traffic in mammalian cells. These missense mutations cause the Charcot−Marie Tooth type 2B (CMT2B) phenotype and target highly conserved amino acid residues. However, nothing is known about how these mutations affect specifically sensory and/or motory neurons, and lead to an axonal pathology in CMT2B. This issue is particularly challenging considering that Rab7 is a ubiquitous protein. This proposal plans to start to investigate the molecular mechanism responsible for the development of the disease. Indeed, we will analyze the behavior of the Rab7 mutant proteins in the cell. In particular, we plan i) to establish whether and how the mutations affect the activity of the protein using endocytosis and biochemical assays, and ii) whether and how the mutated proteins are able to interact with the known Rab7 effector proteins. In addition, iii) we will screen for new Rab7 effector proteins searching for possible interactors specific for peripheral nervous system. Understanding how dysfunction of Rab7 causes sensory and motor neuropathy in patients with CMT2B will be instrumental to gain insights in the pathogenesis of this group of disorders, and will open the way to identify therapeutic approaches