The Pathogenesis of Familial Dysautonomia is Explained by Abnormal Elp1‐dependent Retrograde Nerve Growth Factor (NGF) Signaling

Abstract

Familial Dysautonomia (FD; Riley‐Day Syndrome; HSAN3) is characterized by debilitating sensory and sympathetic neuropathy. It is caused by a germline mutation of the Elp1 gene that leads to mis‐splicing and loss of Elp1 protein primarily in sympathetic and sensory neurons. How Elp1 functions in the pathogenesis of FD in developing and adult disease‐vulnerable neurons is not known.We generated conditional knockout mice with Elp1 ablated specifically in sympathetic neurons and found that they have increased sympathetic neuron apoptosis, target tissue innervation abnormalities and dysautonomia similar to humans with FD. Sympathetic neurons isolated from Elp1‐deficient mice showed no abnormalities in their survival when they were completely immersed in medium containing NGF, a neurotrophic factor that is required for their survival and differentiation. By contrast, when sympathetic neurons were grown in partitioned cultures with NGF present only in the distal axon compartment to emulate the way NGF is acquired from peripheral target tissues in vivo, Elp1‐deficient neurons were found to have profound abnormalities in survival and axon outgrowth compared to wild type neurons. Thus, retrograde NGF signaling in sympathetic neurons is dependent on Elp1, and abnormalities in retrograde signaling explain the poor sympathetic neuron survival, abnormal target tissue innervation and resulting dysautonomia in patients with FD. Future studies to define how Elp1 regulates NGF retrograde transport and signaling may make it possible to target new signaling pathways for treating FD and other autonomic neuropathies for which no effective therapies currently exist (Support: NIH NICHD and OD).