The effect of ALS-linked gene disruption on Drosophila behaviour

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disorder (MND) characterised by lower motor neuron (MN) loss leading to progressive muscle weakness and eventually, respiratory paralysis. It is the most common type of MND accounting for around 85% of the cases, most of which are sporadic while about 10% are familial. A large number of genes have been linked to familial ALS, most of which code for proteins involved in mRNA processing. Spinal muscular atrophy (SMA) is the commonest MND in children and is caused by mutations in SMN1. The functional SMN protein forms a complex with Gemins and unr interacting protein (unrip) which has a function in small nuclear ribonucleo protein (snRNPs) formation. Gemin3, a DEAD-box RNA helicase is a key member of the SMN complex. A link between ALS and SMA has been identified and it was found that higher levels of SMN in MNs increase survival in both conditions. The present study made use of Drosophila melanogaster as a model organism to investigate the presence of a genetic interaction between Gemin3 and the commonest ALS-linked genes: SOD1, TARDBP, FUS and C9orf72. Models were created expressing mutant forms of the ALS genes together with Gem3BART, a Gemin3 hypomorph, within the muscle tissue by using the Mef2-GAL4 driver. Investigations were then carried out to assess the mobility phenotype of these models either in the larval or in the adult stages. Larval mobility assays, pupal axial ratio analysis, climbing assays, flight assays and survival analysis were used to determine the extent of ALS-associated phenotypes in the models generated. A significant reduction in mobility indicated an enhancing effect by the ALS-linked genes on an SMA fly model, therefore supporting the hypothesis of shared pathophysiology between the two MNDs. A better understanding of the shared mechanism of disease can potentially lead to novel therapeutic strategies that can be targeted to ALS and SMA patients.