Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS

Our results show that the expression of wild-type Fus/Caz or FusR521G induced progressive toxicity in multiple tissues of the transgenic flies in a dose- and age-dependent manner. The expression of Fus, Caz, or FusR521G in motor neurons significantly impaired the locomotive ability of fly larvae and adults. The presynaptic structures in neuromuscular junctions were disrupted and motor neurons in the ventral nerve cord (VNC) were disorganized and underwent apoptosis. Surprisingly, the interruption of Fus nuclear localization by either deleting its nuclear localization sequence (NLS) or adding a nuclear export signal (NES) blocked Fus toxicity. Moreover, we discovered that the loss of caz in Drosophila led to severe growth defects in the eyes and VNCs, caused locomotive disability and NMJ disruption, but did not induce apoptotic cell death.These data demonstrate that the overexpression of Fus/Caz causes in vivo toxicity by disrupting neuromuscular junctions (NMJs) and inducing apoptosis in motor neurons. In addition, the nuclear localization of Fus is essential for Fus to induce toxicity. Our findings also suggest that Fus overexpression and gene deletion can cause similar degenerative phenotypes but the underlying mechanisms are likely different.Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) is a motor neuron disease that causes a disabling condition whereby the degeneration of motor neurons causes progressive muscle weakness and leads to death usually within five years of disease onset [1]. Most cases of ALS occur sporadically, however a small percentage of cases are inherited. Several ALS genes have been identified, and mutations within them can lead to familial ALS [2], including Cu/Zn superoxide dismutase (SOD1) [3], TDP-43 [4] and Fused in sarcoma (Fus) [5-8]. In addition to familial ALS, Fus mutations are also implicated in sporadic ALS cases [9-11]. Both Fus and TDP-43 are DNA- and RNA-binding proteins. While TDP-43 has been intensivel