Understanding Neuronal Cell type-Specific Dysregulation in Familial Dysautonomia

Familial dysautonomia (FD), also known as HSAN type III or Riley-Day syndrome, is a rare, fatal, congenital sensory and autonomic neuropathy caused by a splicing mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in variable tissue-specific skipping of exon 20 with a corresponding reduction of ELP1 protein, mainly in the central and peripheral nervous systems. Patients with FD have a complex neurological phenotype with diminished pain and temperature perception, decreased or absent myotatic reflexes, proprioceptive gait ataxia, and progressive retinal degeneration. ELP1 is reduced in both the central and peripheral nervous systems; however, for reasons that are still unknown, ELP1 reduction preferentially impacts peripheral neurons. While the development of a splicing modulator therapy to treat FD patients has been a primary focus of my laboratory, over the past several years, we have also worked to develop and characterize several mouse models for FD, to elucidate the developmental pathways that are disrupted by ELP1 reduction, to identify genes that are specifically dysregulated in the peripheral nervous system (PNS) and to evaluate the phenotypic consequences of ELP1 splicing correction. Despite remarkable progress in each of these areas, there are still key gaps in our understanding of the molecular mechanisms underlying the cell-type-specific neuronal degeneration that characterized FD. We know that mis- splicing of ELP1 occurs at different levels in all cell types, but it is much worse in neurons. We also know that subpopulations of peripheral neurons are exquisitely sensitive to the loss of ELP1, but we don’t know precisely which cell types or the underlying transcriptomic changes that lead to specific cell loss in FD. It is this overarching question that lays the foundation for the Aims of this renewal application. We have assembled an excellent team with varied expertise, and together we will 1) identify cell-type specific dysregulated genes and networks in the nervous system of our FD mice 2) spatially characterize ELP1 mis-splicing and its contribution to cell-type-specific gene dysregulation in DRG and retina and 3) define cell-type-specific pathogenetic mechanisms and validate the dysregulated gene networks using human neuronal models of FD. This study will not only unravel the molecular mechanisms of cell-type specific degeneration in FD but will also shed light on the role of ELP1 and Elongator in neuronal gene regulation and how its disruption leads to human developmental neuropathies.