Ricerc@Sapienza

SMA is a neurodegenerative disease caused by a deficiency of the Survival Motor Neuron (SMN) protein. The aim of this project is to identify factors involved in the snRNPs biogenesis pathway, able to ameliorate neurodegenerative phenotypes leading to SMA. SMN and TGS1 are strickly linked to snRNPs maturation. We recently demonstrated that TGS1, an S-adenosyl-L-methionine dependent methyltransferase responsible for snRNAs cap trimethylation, physically interacts with all subunits of Drosophila Smn complex and that both dTgs1 and Smn are required for viability of retinal progenitor cells. Downregulation of both genes leads to a reduced eye size and cell death of the retinal precursors. Importantly, overexpression of dTgs1 partially rescues the eye defects caused by Smn depletion, and vice versa, suggesting that TGS1 acts as a conserved SMN modifier and it could be potentially pointed as a possible therapeutic target for combinatorial SMA therapy. Furthermore, expression of human TGS1 transgene rescues the mutant phenotype caused by dTgs1 loss both in flies (1) and worms, underlying its evolutionarily conservation in different species. Fly eye imaginal discs could provide evidence on the mechanisms of cell death in dTgs1 and Smn depleted neuroepithelium, allowing to explore how dTgs1 and Smn cooperate to protect against neurodegeneration. Drosophila eye imaginal discs is a promising venue which will offer a convenient background to screen for novel genetic modifiers and interactors of TGS1 and SMN in order to highlight sensitive nodes in the complex circuitries that protect neuronal cells. These modifiers could help to devise new therapies for SMA.