The effect of survival motor neuron (smn)-gemins complex disruption on drosophila behaviour during early stages of development

Abstract

Spinal muscular atrophy (SMA) is a motor neuron degenerative disorder characterised by muscle weakness and can lead to death in severe cases. Deletion or mutation of the Survival Motor Neuron 1 (SMN1) gene causes SMA since the SMN protein produced from the second gene SMN2 is not sufficient for the survival and function of the neuromuscular system. SMN protein forms complexes with Gemins 2-8 and Unrip which together regulate the assembly of small nuclear ribonucleo-proteins (snRNPs) which in turn make up the spliceosome. In this study, Drosophila melanogaster was used to see whether disruption of the SMN-Gemins complex has an effect on the flies at early stages of development. To this end, Gem3BART, a weak hypomorphic mutant of Gemin3, was coupled with increased or decreased levels of SMN, Gemin2 or Gemin5 in the drosophila musculature. The effects of these genetic manipulations on neuromuscular function were investigated by observing larval body wall contractions and muscle contraction during pupariation. Gem3BART was also coupled with TDP-43, a protein that is mutated in a subset of patients with amyotrophic lateral sclerosis (ALS), and Glos, a newly-discovered Gemin3-interacting partner. Perturbation of different SMN-Gemins complex components or TDP-43 in combination with Gemin3 loss-of-function was found to reduce larval mobility and caused the pupae to have an increased axial ratio. These findings show that the function of the SMN-Gemins complex is crucial for the health of the flies starting from an early stage of development. Further understanding of the role of the SMNGemins complex in the neuromuscular system can bring us closer to deciphering the pathophysiology of SMA which would ultimately help in the discovery of novel effective treatments for this devastating disorder.