The goal of this proposal is to understand why reductions in the level of the IKAP protein cause the Hereditary Sensory and Autonomic Neuropathy Type III, Familial Dysautonomia (FD;also called Riley Day Syndrome). This disease is both a developmental and a progressive disorder. It is marked by tachycardia, orthostatic hypotension which results in frequent fainting and autonomic vomiting "crises", pulmonary problems, renal failure and musculoskeletal manifestations including scoliosis, ataxia and weakness. This disease not only devastates the functioning of the Autonomic Nervous System, but also is marked by severe deficits in pain and temperature sensation and has CNS manifestations. FD is due to a mutation in the gene IKBKAP, in a splice acceptor site (IVS20+6T>C;99.5% of patients) that causes the transcription of a truncated mRNA which is targeted for nonsense-mediated decay. The function of the encoded protein, IKAP, is unresolved. It clearly plays an essential role in that mice that are completely null for Ikbkap die by E10 due to failure in neurulation and vasculogenesis. To determine what role IKAP serves in the nervous system and why its absence results in FD, we have made 2 conditional-knock out mouse models for the disease in which Ikbkap is deleted either from the neural crest (using a Wnt1-cre), or from neurons in the central nervous system (CNS), but not the peripheral nervous system (PNS;using a Ta1tubulin-cre). The Wnt1-cre/Ikbkap mice die within 24 hrs of birth and analyses of their PNS demonstrates a recapitulation of the human disease with significant reductions in sympathetic, parasympathetic and TrkA+ pain and temperature sensing neurons and thus provides an excellent model for determining the developmental disruptions in the disease. We found that the reduction in PNS neurons during development is due to apoptosis of both progenitor cells and post-mitotic neurons. The Ta1tubulin-cre/Ikbkap also faithfully recapitulates classic, but distinct, hallmarks of FD including scoliosis, hind limb weakness, and gait ataxia. These mice die on average at 5 months and their condition degenerates as they age, thus they provide an excellent system in which to study the progressively degenerative mechanisms that mark FD. These results indicate not only is deletion of Ikbkap in the nervous system sufficient to cause FD, but that we have two independent models in which we can dissect the functions of IKAP in the CNS and PNS, during development vs. progression in the adult. Since the Autonomic Nervous system (ANS) is a circuit that includes both CNS and PNS components, we propose here to take a system wide approach to determine the function of IKAP in both the CNS and PNS. With an understanding of the key pathways which require IKAP, the long term goal is to develop strategies to prevent the progressive degeneration of both CNS and PNS neurons in FD and the other HSANs.
Familial Dysautonomia (FD) is a genetic disease that devastates the autonomic nervous system - that part of the nervous system that maintains homeostasis, that is, our unconscious ability to adjust our blood pressure and control all of of organs. Should that system fail, as in FD, patients faint frequently, develop frequent bouts of pneumonia, and have vomiting crises. The disease is due to a mutation in the gene IKBKAP, whose function is unclear. Our goal is to understand what the function of this gene is in the nervous system and why its reduction leads to FD with the long term goal of developing therapeutics to prevent the progressive death of neurons that is a hallmark of this disease.