By exploiting the functional overlap between the human (h-) and fruit fly (d-) TDP-43 orthologs (Ayala et al., 2005), different Drosophila models carrying the targeted disruption of the TDP-43 gene have being generated and virtually all exhibit ALS-like neuromuscular deficits (Romano et al., 2012), indicating a loss of function of TDP-43 being central to the pathogenesis (Buratti and Baralle, 2009; Chen-Plotkin et al., 2010; Da Cruz and Cleveland, 2011; Lee et al., 2012). This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.