The Familial Dysautonomia disease gene, Ikbkap/Elp1, is required in the developing and adult central nervous system

Abstract

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.