Abstract
ABSTRACTFamilial 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 a decrease in the synthesis of the encoded protein IKAP (also known as ELP1). Small non-coding RNAs known as microRNAs (miRNAs) are important post-transcriptional regulators of gene expression and play an essential role in the nervous system development and function. To better understand the neuronal specificity of IKAP loss, we examined expression of miRNAs in human olfactory ecto-mesenchymal stem cells (hOE-MSCs) from five control individuals and five FD patients. We profiled the expression of 373 miRNAs using microfluidics and reverse transcription coupled to quantitative PCR (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 had been 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, supporting a potential interaction between NOVA1 and IKAP. Taken together, these results reinforce the choice of miRNAs as potential therapeutic targets and suggest that NOVA1 could be a regulator of FD pathophysiology.
Highlights
Familial dysautonomia (FD, known as Riley Day syndrome or hereditary sensory and autonomic neuropathy type III; MIM 223900) is an autosomal recessive disorder that occurs with a carrier frequency of 1 in 30 in the Ashkenazi Jewish population (Scott et al, 2010)
Initial testing for IKBKAP mRNA alternative splicing in hOE-MSCs To detect the differential expression of miRNAs in FD compared to control hOE-MSCs, total RNA was extracted from five healthy control and five FD hOE-MSC cultures
To ensure that we would be able to establish links between mRNA and miRNA expression in hOE-MSCs, we first conducted an initial assessment of IKBKAP mRNA isoforms by reverse transcription coupled to quantitative PCR (RT-qPCR)
Summary
Familial dysautonomia (FD, known as Riley Day syndrome or hereditary sensory and autonomic neuropathy type III; MIM 223900) is an autosomal recessive disorder that occurs with a carrier frequency of 1 in 30 in the Ashkenazi Jewish population (Scott et al, 2010). This disease is characterized by an incomplete development and a progressive depletion of autonomic and sensory neurons No cure is currently available for this neurodegenerative disease and treatment is aimed at controlling symptoms and reducing complications
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