Abstract
ABSTRACTFamilial dysautonomia (FD) is an autosomal recessive disorder marked by developmental and progressive neuropathies. It is caused by an intronic point-mutation in the IKBKAP/ELP1 gene, which encodes the inhibitor of κB kinase complex-associated protein (IKAP, also called ELP1), a component of the elongator complex. Owing to variation in tissue-specific splicing, the mutation primarily affects the nervous system. One of the most debilitating hallmarks of FD that affects patients' quality of life is progressive blindness. To determine the pathophysiological mechanisms that are triggered by the absence of IKAP in the retina, we generated retina-specific Ikbkap conditional knockout (CKO) mice using Pax6-Cre, which abolished Ikbkap expression in all cell types of the retina. Although sensory and autonomic neuropathies in FD are known to be developmental in origin, the loss of IKAP in the retina did not affect its development, demonstrating that IKAP is not required for retinal development. The loss of IKAP caused progressive degeneration of retinal ganglion cells (RGCs) by 1 month of age. Mitochondrial membrane integrity was breached in RGCs, and later in other retinal neurons. In Ikbkap CKO retinas, mitochondria were depolarized, and complex I function and ATP were significantly reduced. Although mitochondrial impairment was detected in all Ikbkap-deficient retinal neurons, RGCs were the only cell type to degenerate; the survival of other retinal neurons was unaffected. This retina-specific FD model is a useful in vivo model for testing potential therapeutics for mitigating blindness in FD. Moreover, our data indicate that RGCs and mitochondria are promising targets.
Highlights
Familial dysautonomia (FD; MIM223900) is an autosomal recessive congenital neuropathy that is caused by an intronic mutation in the IKBKAP gene, which encodes the inhibitor of κB kinase complexassociated protein (IKAP), called elongator complex protein 1 (ELP1) (Anderson et al, 2001; Dong et al, 2002; Riley et al, 1949; Slaugenhaupt et al, 2001)
We demonstrated that loss of IKAP in the retinal ganglion cells (RGCs) caused a slow, progressive RGC degeneration most severely in the temporal retina, later followed by indirect photoreceptor loss and complete retinal disorganization
Ikbkap was deleted from the majority of central nervous system (CNS) neurons and approximately 40% of peripheral nervous system (PNS) neurons; whether all or some of these phenotypes were directly due to autonomous loss of Ikbkap in retinal cells could not be determined
Summary
Familial dysautonomia (FD; MIM223900) is an autosomal recessive congenital neuropathy that is caused by an intronic mutation in the IKBKAP gene, which encodes the inhibitor of κB kinase complexassociated protein (IKAP), called elongator complex protein 1 (ELP1) (Anderson et al, 2001; Dong et al, 2002; Riley et al, 1949; Slaugenhaupt et al, 2001). A point-mutation in intron 20 results in Department of Cell Biology and Neuroscience, Montana State University, Bozeman, MT 59717, USA. Either as a direct or indirect consequence of this altered translation, Ikbkap conditional knockout (CKO) neurons exhibit impaired axonal transport, target innervation and cell survival (Abashidze et al, 2014; Chaverra et al, 2017; Close et al, 2006; George et al, 2013; Hunnicutt et al, 2012; Jackson et al, 2014; Johansen et al, 2008; Lefler et al, 2015; Naftelberg et al, 2016; Naumanen et al, 2008; Tourtellotte, 2016; Ueki et al, 2016)
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