TDP-43-mediated Amyotrophic Lateral Sclerosis: new/hidden insights from Drosophila

Transactive response DNA-binding protein 43 (TDP-43) is a key factor in motor neurons andrelated neurodegenerative disorders, and the presence of cytoplasmic aggregates of TDP-43 is amajor hallmark of diseases such Amyotrophic lateral sclerosis (ALS) and frontotemporal lobardegeneration (FTLD). Nevertheless, little is known about the exact mechanism of action of TDP-43-mediated toxicity. Drosophila melanogaster is acknowledged as a powerful genetic model forstudying the genetic inheritance and the behavioral and developmental processes associated withhuman neurodegenerative diseases, including ALS. To better understand the possible roles andpotential pathogenic mechanisms of the TDP-43 protein in the pathogenesis of ALS, we haveperformed a transcriptomic analysis of larvae from a Drosophila model knock-out (KO) for the geneTBPH, the fly TDP-43 ortholog. Interestingly, the gene ontology analysis has highlighted somepathways not yet associated with this pathology and this model. In particular, we have identifiedseveral genes encoding for serine proteases, a class of enzymes that in the SNC modulate thedegradation of neurotransmitters and influence synaptic plasticity. Our work provides insights intonovel pathological mechanisms underlying the disease, thereby opening new pathways for drugdiscovery.