Hereditary peripheral neuropathies (also known as hereditary motor sensory neuropathies, HMSN) are among the most common genetic diseases affecting the nervous system. The mildest form of human peripheral neuropathy, Charcot-Marie-Tooth (CMT) disease, causes progressive deterioration of both motor and sensory nerves, muscular atrophy, and chronic pain/fatigue in affected individuals. A majority of inherited peripheral myelinopathies are caused by duplication of a critical myelin gene, Peripheral Myelin Protein 22 (PMP22), which is classified as CMT1A. Since this disorder results from gene dosage effects, achieving a slight (<2-fold) reduction in PMP22 expression would effectively treat this inherited myelinopathy. Recent proof-of-principle studies using candidate compounds to reduce PMP22 expression levels have shown beneficial effects in rodent models of CMT1A. Before such candidate compounds enter clinical trials, it will be critical to achieve a comprehensive understanding of their molecular targets and how they impact PMP22 regulation. Our recent studies of PMP22 regulation have elucidated novel regulatory elements controlled by two major regulators of Schwann cell development-Egr2/Krox20 and Sox10-and the goal of this proposal is to test the function of these elements by using genome editing to delete them in the endogenous PMP22 locus. In addition, we will use zebrafish analysis to elucidate the developmental control of these enhancers. This proposal will also explore the function of cooperating transcription factors that amplify PMP22 expression to the high levels found in myelinating Schwann cells. Finally, using the mechanistic analysis that we have developed, we propose to identify the molecular targets of proteasome inhibitors, which are a candidate treatment for CMT1A as they have been recently identified in a drug screen to lower the expression level of PMP22.
One of the most common inherited diseases affecting the nervous system is Charcot-Marie- Tooth disease, affecting approximately 1 in 3000 individuals. The most common cause of this disease is a duplication of the PMP22 gene (resulting in CMT1A). This proposal is designed to elucidate the mechanism of PMP22 regulation to enable identification of mechanistic targets of potential therapies for CMT1A.