Abstract

Familial dysautonomia (FD) is a rare neurodegenerative disease caused by a mutation in intron 20 of the IKBKAP gene (c.2204+6T>C), leading to tissue-specific skipping of exon 20 and decrease of IKAP/hELP1 synthesis. Small non-coding RNAs, microRNAs (miRNAs) are important posttranscriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP/hELP1 loss, we examined expression of miRNAs, in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from 5 control individuals and 5 FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative polymerase chain reaction (RT-qPCR) on two biological replicate series of hOE-MSC cultures from healthy controls and FD patients. This led to the total identification of 26 dysregulated miRNAs in FD, validating the existence of a miRNA signature in FD. We then selected the nine most discriminant miRNAs for further analysis. The signaling pathways affected by these dysregulated miRNAs were largely within the nervous system. In addition, many targets of these dysregulated miRNAs were previously demonstrated to be affected in FD models. Moreover, we found that four of our nine candidate miRNAs target the neuron-specific splicing factor NOVA1. We demonstrated that overexpression of miR-203a-3p leads to a decrease of NOVA1, counter-balanced by an increase of IKAP/hELP1, supporting a potential interaction between NOVA1 and IKAP/hELP1. Altogether, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be involved as a regulator of FD pathophysiology.