A Drosophila model for Spinal Muscular Atrophy (SMA): identification and characterization of Smn interactors and phenotypic modifiers

Spinal Muscular Atrophy (SMA) is caused by nerve degeneration and muscle dysfunction. The gene responsible for SMA is SMN (Survival of Motor Neurons); defects in this gene reduce the dosage of the SMN protein, which is essential for nerve cell function. Motor neurons (nerve cells), with their specialized structure, are particularly sensitive to even subtle defects in SMN dosage. Why SMN is so critical in nerve cells and how its function is finely coordinated in these cell types is still obscure. Current therapeutic approaches are aimed at improving SMN activity by increasing the dosage of the SMN protein in the cells of SMA patients. Our goal is the identification of novel proteins that cooperate with SMN and modulate its function. These “SMN modifiers” might represent novel therapeutic tools or targets for SMA. We devised a genetic approach in the fruit fly, Drosophila melanogaster, to identify new SMN modifiers. Drosophila is an excellent model for SMA, as flies with a reduced SMN dosage recapitulate several features of SMA patients both at the molecular and the neuromuscular level. We already discovered two SMN partners, which function in the same cell compartments as SMN; when the activity of these proteins is reduced, flies exhibit locomotion defects similar to those caused by loss of SMN function. We plan to explore how these proteins cooperate with SMN and whether they can modulate SMN function in specific subtypes of nerve cells. Understanding which SMN partners contribute to preserve the health and stability of the nervous cells is an essential step towards developing new strategies to ameliorate the deleterious effects of a reduced SMN dosage.