Grant: Doctoral Research Award - Priority Announcement: Amyotrophic Lateral Sclerosis

In the last few years, ALS-causing mutations have been discovered in several genes involved in RNA metabolism, such as TARDBP (coding for TDP-43) and FUS, two structurally and functionally related DNA/RNA binding proteins. Zebrafish are optimal for the development of genetic models of ALS, as the zebrafish embryos develop externally and are optically transparent, allowing for fluorescent labelling of live cells. We have previously shown that zebrafish transiently expressing mutated TDP-43 and FUS develop motoneuron defects, leading to a motor phenotype such as reduced motility and abnormal motoneuron axonal outgrowth (Kabashi et al., 2010; Armstrong et al., 2013a and b). Similar results are obtained in mutant TARDBP stable transgenic lines that I have developed during my M.Sc and the beginning of my PhD. Using transient transgenic techniques, we have shown that the genes TARDBP and FUS work in the same pathway (Kabashi et al., 2011), establishing the beginning of a genetic network of ALS. For this PhD project, we propose to use our different genetic models of ALS to study transcriptome modifications induced by ALS-causative mutations of FUS and TARBDP, using next-generation RNA sequencing. We will compare the modifications in all our genetic models to find commonly altered genes as well as commonly altered pathways, in our stable transgenic lines and our transient transgenics. We will further determine if these commonly modified genes or pathways could be the common denominator of the ALS pathology by testing if their overexpression or downregulation in wild-type zebrafish embryos can cause an ALS phenotype similar to the one we observe in our genetic models of ALS. We will thus identify genes that are commonly misregulated due to ALS-causing mutations of TARDBP and FUS, providing us with a better understanding of the pathophysiology of ALS, and opening new possibilities for its pathomechanism, opening new doors for therapeutics.