Assessment of riluzole mechanism of action in Drosophila melanogaster models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurons death and the formation of cytosolic inclusions, mainly composed of the protein TDP-43. In physiological conditions TDP-43 is predominantly found in the nucleus, where it regulates the expression of target mRNAs, while in pathological conditions it accumulates in the cytoplasm and forms aggregates after being hyper-phosphorylated by the protein kinase CK1δ. At the level of astrocytes, alterations in protein expression due to TDP-43 aggregation might lead to glutamate accumulation in synaptic clefts, resulting in excitotoxicity and motor neurons death. All approved ALS treatments are mildly effective, among them, riluzole is the most widely used but its mechanism of action is still unknown. The aims of this project are to assess the role of riluzole in ALS and evaluate its protective effects, in vivo, using Drosophila melanogaster as experimental model. Our working hypothesis is that CK1δ could be a possible target of riluzole, whose inhibition could prevent the aggregation of TDP-43 and favor the expression of the glutamate transporter in astrocytes, with the consequent reduction of cell death due to excitotoxicity. The final aim is to validate the therapeutic potential of more potent and selective CK1δ inhibitors.