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, known as familial dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit (ELP1) for a multi-subunit complex known as Elongator. Since mutations in other Elongator subunits (ELP2 to ELP4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential requirement for Ikbkap in the CNS of mice. The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40. While signs and pathology of FD have been noted in the CNS, the clinical and research focus has been on the sensory and autonomic dysfunction, and no genetic model studies have investigated the requirement for Ikbkap in the CNS. Here, we report, using a novel mouse line in which Ikbkap is deleted solely in the nervous system, that not only is Ikbkap 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 includes impairments in learning and memory. Collectively, these data reveal an essential function for Ikbkap that extends beyond the peripheral nervous system to CNS development and function. With the identification of discrete CNS cell types and structures that depend on Ikbkap, novel strategies to thwart the progressive demise of CNS neurons in FD can be developed.

Elongator complex is required for long-term olfactory memory formation in Drosophila

“…Prior studies have established that RU486-treatment itself is without behavioral effects on control genotypes (Mao et al 2004;Tan et al 2013;Qian et al 2015). Recently, Chaverra et al (2017) deleted elp1 function throughout the nervous system of the mouse beginning at E11 to model the nervous system disruptions found in FD. The mutant mosaic mice exhibit a spectrum of phenotypes, including small size, unsteady gait, microcephaly, reduced motor neuron number, CNS neurodegeneration, reduced anxiety, and impairment in a long-term form of spatial memory.…”

“…Mice null for IKBKAP/elp1 do not survive beyond embryonic day 12.5; this lethality is rescued by expression of the human IKBKAP transgene (Chen et al 2009). Elp1 mutations in the mouse produce neuronal death in the PNS and abnormal development of the CNS (Jackson et al 2014;Chaverra et al 2017). Human genome association experiments have also linked Elp3 with ALS (Simpson et al 2009;Kwee et al 2012).…”

Animal and cellular models of familial dysautonomia

“…Interestingly, two mouse studies reported that in contrast to the pain and temperature sensory afferents, proprioceptors develop and survive normally in the absence of IKAP, but it’s not yet been determined whether they degenerate in adulthood. Since α-motor neurons innervating the neuromuscular junction degenerate in an FD mouse model [54], it’s possible that γ-motor neurons might also degenerate and thereby indirectly affect the integrity of proprioceptors and muscle spindle function.…”

“…Using a pan-neuronal Cre to delete Ikbkap , Chaverra et al, 2017, generated a Tuba1a-Cre; Ikbkap LoxP/LoxP CKO mouse in which Ikbkap is deleted in both the central nervous system (CNS) and PNS beginning in early development (approximately E12.5) [54]. Since CNS pathology has been documented in FD [55, 56] and because mutations in other Elongator subunits ( ELP2-4 ) are associated with CNS disorders, the goal of this study was to investigate a potential CNS requirement for Ikbkap .…”

Prevalence and characteristics of sleep-disordered breathing in familial dysautonomia

“…The amygdala and the hippocampal head are specifically involved in breathing control and the genesis of CA. 22 Because the IKBPAP gene is required for the normal development of the CNS and it is highly expressed in amygdala and hippocampus, 23 it is conceivable that abnormal development and maturation of these regions may underlie the high frequency of central apneas during the pediatric age in patients with FD. As these regions mature with age, CAs are less frequent.…”