a drosophila model of als human als-associated mutation in vap33a suggests a dominant negative mechanismals的果蝇模型人类als-associated突变vap33a表明显性负机制.pdfVIP

A Drosophila Model of ALS: Human ALS-Associated Mutation in VAP33A Suggests a Dominant Negative Mechanism 1 1 2 1 Anuradha Ratnaparkhi , George M. Lawless , Felix E. Schweizer , Peyman Golshani , George R. Jackson1,3* 1 Department of Neurology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America, 2 Department of Neurobiology, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America, 3 Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, United States of America Abstract ALS8 is caused by a dominant mutation in an evolutionarily conserved protein, VAPB (vesicle-associated membrane protein (VAMP)-associated membrane protein B)/ALS8). We have established a fly model of ALS8 using the corresponding mutation in Drosophila VAPB (dVAP33A) and examined the effects of this mutation on VAP function using genetic and morphological analyses. By simultaneously assessing the effects of VAPwt and VAPP58S on synaptic morphology and structure, we demonstrate that the phenotypes produced by neuronal expression of VAPP58S resemble VAP loss of function mutants and are opposite those of VAP overexpression, suggesting that VAPP58S may function as a dominant negative. This is brought about by aggregation of VAPP58S and recruitment of wild type VAP into these aggregates. Importantly, we also demonstrate that the ALS8 mutation in dVAP33A interferes with BMP signaling pathways at the neuromuscular junction, identifying a new mechanism underlying pathogenesis