The effect of Survival Motor Neuron (SMN) : gemins complex disruption on Drosophila behaviour

Abstract

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are motor neuron diseases which cause progressive loss of movement and eventually paralysis. In the case of SMA, this is due to the loss of motor neurons from the spinal cord, secondary to a Survival of Motor Neuron (SMN) gene mutation. This is commonly a deletion in the SMN1 gene. Humans possess a second gene, SMN2, which produces a truncated protein that cannot compensate for the nonfunctional SMN protein produced by the mutated SMN1 gene. Therefore the patient is left without functional SMN, which leads to SMA. SMN is not found alone, but complexed with Gemins 2-8 and Unr-interacting protein (UNRIP). Together, these proteins are involved in the biosynthesis of small nuclear ribonucleoproteins (snRNPs), which make up the spliceosome. On the other hand, one of the causes of ALS is the formation of cytoplasmic aggregates of transactive response DNA binding protein 43 (TDP-43) in neuronal cells, resulting in neurodegeneration. In this study, Drosophila melanogaster was used as a model to investigate the effect of two Gemin3 transgenes: Gem3ΔN and Gem3BART on Drosophila behaviour when expressed in different tissues. Gem3BART was found to have grievous effects on larval behaviour when expressed both muscularly and neuronally. Gem3ΔN on the other hand, had no significant effect on behaviour when expressed in the brain of adult flies. However, Gemin3 aggravated behaviour in flies expressing TDP-43 in the brain, showing commonalities in the pathways underlying SMA and ALS, which may suggest that these two diseases are linked. These findings suggest that treatments that are effective in SMA patients can also be targeted to treat ALS.