Pluto Bioinformatics

GSE101097: A regulatory circuitry between the Gria2 mRNA and miR-409/miR-495 is altered in mESC-derived motor neurons carrying an ALS-associated FUS mutation

Bulk RNA sequencing

Mutations in FUS/TLS have been genetically associated to Amyotrophic Lateral Sclerosis (ALS). Since FUS is a multifunctional protein involved in the biogenesis and activity of several types of RNAs, the understanding of the molecular basis of ALS pathogenesis should take into account both direct effects of FUS mutation through gain- and loss-of function mechanisms as well as indirect effects due to the crosstalk between different classes of RNAs. To identify how FUS alterations impinge on MN-specific RNA-based circuitries, we performed a transcriptome profiling of small- and long- RNAs of motor neurons derived in vitro from differentiation of mouse Embryonic Stem Cells carrying a knock-in FUS-P517L mutation, corresponding to the human FUS-P525L. Combining ontological, predictive and molecular analyses we found an interesting inverse correlation between several classes of deregulated miRNAs and their corresponding mRNA targets. Among them we validated a circuitry in which the up-regulation of miR-409-3p and miR-495-3p produced the down-regulation of the Gria2 mRNA. This cross-talk is relevant for the ALS pathogenesis since Gria2, encoding for a subunit of the glutamate AMPA receptor, has been already linked to ALS through an excitotoxicity mechanism. Notably, this circuitry resulted deregulated also in heterozygous conditions, which match the genetic background of the human pathology. SOURCE: Pietro Laneve (pietro.laneve@iit.it) - Istituto Italiano di Tecnologia