Genetic restoration of IKAP as a tool to study Familial Dysautonomia

点击翻译按钮获取中文摘要

Familial Dysautonomia (FD) is the most prevalent hereditary autonomic and sensory neuropathy. Individuals affected with FD display dysfunction of the peripheral nervous system already at birth accompanied by abnormally low neuronal numbers in sympathetic and sensory ganglia, which further decline over time. The disorder is caused by mutations in the gene IKBKAP that lead to significant decrease in expression of the protein it encodes, called IKAP. Since IKAP is apparently needed for several cellular processes and FD is a progressive neurodegenerative disorder, much effort has been recently focused in identifying and testing compounds that increase IKAP expression, with the hope that increasing IKAP levels will halt the disease progression and/or reverse some of the disease phenotypes. However, since FD has a strong developmental component, it is unclear to what extent increasing IKAP expression may stop disease progression or significantly improve the clinical features and quality of life of affected individuals. Although testing compounds that increase IKAP levels in mouse models or in patients may answer this question in the long run, determining the timing when the treatments should be initiated and the optimal level of IKAP required for the treatment to be successful represents a Herculean effort. In addition, the possibility of long-term toxic systemic side-effects of such compounds may mask their beneficial effects. Using the Cre-loxP system of recombination, we have generated a unique mouse model for FD that not only recapitulates a large number of the disease phenotypic features, but can also be used to genetically restore IKAP expression at will, thus avoiding the off-target effects of other strategies. With this unique tool in hand, we propose to assess the effects of restoring IKAP expression globally at different time-points using a tamoxifen-inducible Cre transgenic line. Completion of this application will uncover the full potential of FD therapies that aim at increasing IKAP expression levels, guide future research towards complementary therapeutic approaches, and allow for further understanding of the mechanisms underlying FD.