title: ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function.
abstract: Mutations in FUS cause amyotrophic lateral sclerosis (ALS), including some of the most aggressive, juvenile-onset forms of the disease. FUS loss-of-function and toxic gain-of-function mechanisms have been proposed to explain how mutant FUS leads to motor neuron degeneration, but neither has been firmly established in the pathogenesis of ALS. Here we characterize a series of transgenic FUS mouse lines that manifest progressive, mutant-dependent motor neuron degeneration preceded by early, structural and functional abnormalities at the neuromuscular junction. A novel, conditional FUS knockout mutant reveals that postnatal elimination of FUS has no effect on motor neuron survival or function. Moreover, endogenous FUS does not contribute to the onset of the ALS phenotype induced by mutant FUS. These findings demonstrate that FUS-dependent motor degeneration is not due to loss of FUS function, but to the gain of toxic properties conferred by ALS mutations.
authors: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
authors: Aarti
authors: A
authors: Sharma
authors: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
authors: Alexander K
authors: AK
authors: Lyashchenko
authors: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
authors: Lei
authors: L
authors: Lu
authors: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
authors: Sara Ebrahimi
authors: SE
authors: Nasrabady
authors: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
authors: Margot
authors: M
authors: Elmaleh
authors: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
authors: Monica
authors: M
authors: Mendelsohn
authors: Department of Neuroscience, Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA.
authors: Adriana
authors: A
authors: Nemes
authors: Department of Neuroscience, Columbia University, New York, New York 10032, USA.
authors: Juan Carlos
authors: JC
authors: Tapia
authors: Department of Pathology and Cell Biology, Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
authors: George Z
authors: GZ
authors: Mentis
authors: Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 630 W 168th Street, P&S Building, Room 5-423, New York, New York 10032, USA.
authors: Neil A
authors: NA
authors: Shneider
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D009046:Motor Neurons / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000294:innervation / Q000473:pathology*; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism*; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS