title: Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is progressive neurodegenerative disease characterized by the loss of motor function. Several ALS genes have been identified as their mutations can lead to familial ALS, including the recently reported RNA-binding protein fused in sarcoma (Fus). However, it is not clear how mutations of Fus lead to motor neuron degeneration in ALS. In this study, we present a Drosophila model to examine the toxicity of Fus, its Drosophila orthologue Cabeza (Caz), and the ALS-related Fus mutants.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Ruohan
authors.initials: R
authors.lastname: Xia
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Liuqing
authors.initials: L
authors.lastname: Yang
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gal
authors.forename: Haining
authors.initials: H
authors.lastname: Zhu
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure*; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D035362:Transcription Factor TFIID / Q000235:genetics* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; D035362:Transcription Factor TFIID; C094754:caz protein, Drosophila