Ricerc@Sapienza

RNA binding proteins (RBPs) play multiple roles in RNA metabolism and their mutation, delocalization and/or altered expression have been proposed to cause familial and sporadic ALS. Elucidating the underlying molecular mechanisms is of crucial importance to design effective therapeutic approaches. Recently, it has been identified a new RBP involved in FUS-ALS: HuD/ELAVL4 (De Santis et al., 2017; De Santis et al., 2019). New preliminary data show that altered HuD levels are associated with competition between mutant FUS and FMRP for HuD 3'UTR binding. This evidence could induce increased levels of NRN1 and GAP43 and aberrant axon regeneration phenotype (Garone et al. in preparation). This pilot project aims at increasing the scientific confidence in the role of the molecular circuitry involving HuD, FMRP, NRN1 and GAP43 in the context of FUS-ALS.
I expect to clarify the contribution of HuD and its targets, including (but not limited to) NRN1 and GAP43, to early dysfunctions possibly leading to ALS. In particular, I would like to define the contribution of dysregulated HuD to the alteration of RNA metabolism in FUS mutant motoneurons. Moreover, I wish to clarify if the competition between mutant FUS and FMRP represents a pathogenic mechanism downstream of FUS mislocalization in the cytoplasm. Finally, mutant mouse ESC lines generated in this project will be next used to produce mouse models of both FUS and sporadic ALS. So, these evidences could be used for designing new therapeutic strategies and/or as biomarkers in future pre-clinical studies.