Regulation of VAP(P58S) neuroaggregation in a Drosophila model of Amyotrophic Lateral Sclerosis

Abstract

Neuronal protein aggregates are a hallmark of neurodegenerative disease. These cellular inclusions are found in neurons of ALS patients, both sporadic and familial, and are also seen when mutant ALS loci are expressed in animal models. In our study, we find that activity of SOD1/ALS1 and also TOR signalling modulates the formation and/or clearance of the aggregates formed by the ALS8 causative locus, VAPB, in the brain of Drosophila. Our findings support one of the earliest models proposed for ALS, which incorporate oxidative stress as a central feature of the disease. Our investigation experimentally demonstrates that the dynamics of ALS8 aggregation depends on a specific threshold of cellular reactive oxygen species (ROS), as measured by protein and lipid oxidation. This threshold is regulated by SOD1, TOR signalling and wild type VAP levels. The relationships between loci, as detailed in our study, allow insight into the mechanisms by which a neuronal cell could regulate proteostasis. Genetic or environmental factors could trigger change in ROS levels, under physiological conditions, to direct the neuron to a disease state. Our study thus uncovers critical regulatory networks that would be affected during the initiation, progression and onset of motor neuron disease.