Roscovitine’s Effect on D. melanogaster with TDP-43 Nuclear Loss Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurological disease that leads to motor neuron death, causing muscle atrophy and paralysis. The majority of ALS patients die from respiratory failure within 2–5 years. By 2040, the incidence of ALS is predicted to increase worldwide by 70%. ALS has no cure. TDP-43 protein dysfunction is present in ~97% of ALS patients. Past ALS research focused on TDP-43 aggregation in the cytoplasm of neuronal cells; however, loss of TDP-43 from the nucleus is now considered the main contributor to neurodegeneration. Drosophila larvae with dTDP-43 nuclear loss exhibit locomotion deficits and reduced levels of cacophony, a neuronal calcium channel required for neurotransmitter release. When cacophony was restored in dTDP-43 nuclear loss larvae, locomotion was rescued. Roscovitine is a drug that increases calcium influx in neuronal calcium channels, essentially performing the same function as increased cacophony. The purpose and novelty of this research are to determine if a roscovitine supplement can improve the locomotion of a TDP-43 nuclear loss ALS model of Drosophila melanogaster. The larval locomotion assay was used to validate the ALS symptom of muscle weakness. The movements of larvae on an agar plate were recorded. Using ImageJ, the displacements and speeds of the larvae were determined. Results indicate that ALS larvae fed roscovitine performed significantly better on the locomotion assay than ALS larvae fed normal food (p-value < 0.0001). This research provides insight into the role of neuronal calcium channels in TDP-43 nuclear loss and calcium channel agonists’ potential in treating ALS.