Browsing by Author "Murnion, Connor"

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The Familial Dysautonomia disease gene, Ikbkap/Elp1, is required in the developing and adult central nervous system
(2017-02) Chaverra, Marta; George, Lynn; Mergy, Marc; Waller, Hannah R.; Kujawa, Katharine J.; Murnion, Connor; Sharples, Ezekiel; Thorne, Julian; Podgajny, Nathaniel; Grindeland, Andrea; Ueki, Yumi; Eiger, Steven; Cusick, Cassie; Babcock, A. Michael; Carlson, George A.; Lefcort, Frances
Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN Type III, Familial Dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit for a multi-subunit complex Elongator. Since mutations in other Elongator subunits (ELP2-4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential CNS requirement for Ikbkap/Elp1 The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While CNS signs and pathology have been noted in FD, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap/Elp1 in the CNS. Here we report using a novel mouse line in which Ikbkap/Elp1 is deleted solely in the nervous system, that not only is Ikbkap/Elp1 widely expressed in the embryonic and adult CNS, but its deletion perturbs both the development of cortical neurons and their survival in adulthood. Primary cilia in embryonic cortical apical progenitors and motile cilia in adult ependymal cells are reduced in number and disorganized. Furthermore, we report that in the adult CNS, both autonomic and non-autonomic neuronal populations require Ikbkap for survival, including spinal motor and cortical neurons. In addition, the mice developed kyphoscoliosis, an FD hallmark, indicating its neuropathic etiology. Ultimately, these perturbations manifest in a developmental and progressive neurodegenerative condition that include impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap/Elp1 that extends beyond the PNS, to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap/Elp1, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.
Identification of genes regulated by IKBKAP: Investigating why neurons die in the disease Familial Dysautonomia
(2013-03) Murnion, Connor; Lefcort, Frances; Eibs, Amy
Familial Dysautonomia is a disease of the peripheral nervous system caused by a mutation of the IKBKAP gene on human chromosome nine. The goal of this research project is to determine what effect the knock-out of this gene has on transgenic model mice. In particular, it examines why proteins previously found to have altered concentrations in the mutant mice are present in different amounts compared to the control. To look at the expression of these genes, which include neuropeptide Y, parvalbumin, and substance P, the polymerase chain reaction was used to amplify these genes from reverse transcribed RNA isolated from both mutant and control mouse tissue. The PCR products were then run in agarose gel electrophoresis to determine expression levels. Due mostly to a lack of time, the project has yet to produce any conclusive results but work continues in order to obtain evidence concerning gene expression levels in the model mice.