Despite evidence that neurotrophins play an essential role in the development and maintenance of the peripheral nervous system, the mechanisms underlying neurotrophic dysfunction in different human peripheral neuropathies as well as its relevance to the disease process are still not well defined. Familial Dysautonomia (FD) is the most frequent hereditary autonomic and sensory neuropathy. Individuals affected with FD display dysfunction of the peripheral nervous system already at birth accompanied by abnormally low numbers of neurons in sympathetic and sensory ganglia. The disorder is caused by mutations in the gene Ikbkap, which encodes IKAP. With the identification of the gene that causes FD, the mechanisms underlying the disease can now be more clearly delineated. We have generated a mouse model for FD by mutating the mouse Ikbkap gene homolog. To date this is the only model that recapitulates the molecular and pathological features of the disease and thus represents an invaluable and unique tool to determine the mechanisms underlying the disease neuropathology. Based on our preliminary results, the findings that neurotrophic activity is reduced in serum and fibroblasts from FD patients, that IKAP regulates expression of furin (the enzyme required for NGF processing in embryogenesis), and that inhibition of NGF activity recapitulates the disease neuropathology in vivo, we hypothesize that reduced NGF-mediated neurotrophic support underlies FD neuropathology. Using molecular, biochemical, cellular, and genetic approaches we will (1) test the hypothesis that transcriptional regulation of NGF is impaired in our model of FD, (2) test the hypothesis that the reduced biological activity of NGF in our FD mouse model is due to impaired pro-NGF processing and signaling, (3) test the hypothesis that over-expression of NGF and/or furin rescues neuronal cell loss in the developing peripheral nervous system of FD mice. The analyses proposed will not only provide further information into mechanisms underlying FD, but also insight for potential therapeutic intervention. Also it will enhance our understanding of the normal peripheral nervous system development and maintenance.

Public Health Relevance

Peripheral neuropathies affect a significant fraction of the population and are classified as inflammatory, toxic, metabolic (diabetes mellitus) and hereditary neuropathies. Familial Dysautonomia (FD) is the most frequent hereditary neuropathy, and is inevitably fatal. Understanding the mechanisms underlying this disorder will provide insights for potential new therapeutic interventions for FD and for other peripheral nervous system disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Gwinn, Katrina
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University of Tennessee Health Science Center
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Morini, Elisabetta; Dietrich, Paula; Salani, Monica et al. (2016) Sensory and autonomic deficits in a new humanized mouse model of familial dysautonomia. Hum Mol Genet 25:1116-28
Dietrich, Paula; Dragatsis, Ioannis (2016) Familial Dysautonomia: Mechanisms and Models. Genet Mol Biol 39:497-514
Cheishvili, David; Dietrich, Paula; Maayan, Channa et al. (2014) IKAP deficiency in an FD mouse model and in oligodendrocyte precursor cells results in downregulation of genes involved in oligodendrocyte differentiation and myelin formation. PLoS One 9:e94612
Dietrich, Paula; Alli, Shanta; Shanmugasundaram, Revathi et al. (2012) IKAP expression levels modulate disease severity in a mouse model of familial dysautonomia. Hum Mol Genet 21:5078-90
Dietrich, Paula; Yue, Junming; E, Shuyu et al. (2011) Deletion of exon 20 of the Familial Dysautonomia gene Ikbkap in mice causes developmental delay, cardiovascular defects, and early embryonic lethality. PLoS One 6:e27015