Pharmacologic activation of the ATF6 branch of the UPR for therapeutic intervention in CMT1B neuropathy

Hereditary neuropathies are a common problem seen in neurology, in which the membrane that surrounds nerves (called myelin), necessary to properly conduct impulses to muscle, is damaged. Many neuropathies appear in every generation of a stricken family and unfortunately affect children. Although many disease genes have been identified for neuropathies, how disease is caused is still poorly understood, and there is no effective treatment. Genetic studies of hereditary neuropathies strongly suggest that most do not result simply because the affected gene does not work. Instead the disease gene has a toxic effect on the cells in the nerve. In order to understand that toxicity, and to envisage a therapeutic treatment, we study mice containig the mutant gene, that we have shown produce excellent model of the disease. In these mice we have identified the toxic mechanism, known as the unfolded protein response, and we have shown that genetic and pharmacologic modulation of this pathway may ameliorate the disease. In this study we propose to further analyze this pathway and how pharmacological compounds that target it may improve the disease outcome with the final goal to treat hereditary neuropathies.