Drosophila as a model system to dissect the molecular mechanisms of Motor Neuron Disease pathogenesis. (360G-Wellcome-086552_Z_08_Z)

One powerful tool to analyse disease mechanisms is the development of transgenic animal models. hVAPB is the causative gene of a clinically diverse group of Motor Neuron Diseases (MNDs) including Amyotrophic Lateral Sclerosis (ALS), atypical ALS and spinal muscular atrophy. We generated a model for VAP-induced MNDs in Drosophila. Transgenic expression of the mutant protein in the larval neurons causes cell death, locomotion defects and aggregate deposition while a rough and smaller eye phenotyp e is induced by driving the expression of the same protein in the eye. We propose to undertake a genome-wide screen for genetic modifiers that modulate VAP-induced toxicity in the adult eye and, subsequently, validate the modifying activity of these interactors in tissues that are more characteristically affected in MNDs such as brain and motor systems. Recently, it was reported that VAPB could function as a molecular link between Fronto-Temporal Dementia (FTD) and ALS, two diseases with overlap ping clinical features but different aetiology. We intend to carry out a genetic approach aimed at highlighting differences and similarities in the patho-mechanisms underlying FTD and ALS. Taken together, the proposed research should lead to new insights into the pathogenesis of MNDs and provide new therapeutic targets for these disorders.