title: ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation.
abstract: Mutations in Fused in Sarcoma/Translocated in Liposarcoma (FUS) cause familial forms of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive axonal degeneration mainly affecting motor neurons. Evidence from transgenic mouse models suggests mutant forms of FUS exert an unknown gain-of-toxic function in motor neurons, but mechanisms underlying this effect remain unknown. Towards this end, we studied the effect of wild type FUS (FUS WT) and three ALS-linked variants (G230C, R521G and R495X) on fast axonal transport (FAT), a cellular process critical for appropriate maintenance of axonal connectivity. All ALS-FUS variants impaired anterograde and retrograde FAT in squid axoplasm, whereas FUS WT had no effect. Misfolding of mutant FUS is implicated in this process, as the molecular chaperone Hsp110 mitigated these toxic effects. Interestingly, mutant FUS-induced impairment of FAT in squid axoplasm and of axonal outgrowth in mammalian primary motor neurons involved aberrant activation of the p38 MAPK pathway, as also reported for ALS-linked forms of Cu, Zn superoxide dismutase (SOD1). Accordingly, increased levels of active p38 MAPK were detected in post-mortem human ALS-FUS brain tissues. These data provide evidence for a novel gain-of-toxic function for ALS-linked FUS involving p38 MAPK activation.
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Reddy Ranjith K
authors.initials: RR
authors.lastname: Sama
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Fallini
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Gatto
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: McKeon
authors.affiliation: Department of Genetics, School of Medicine, Yale University, New Haven, CT, USA.|Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Yuyu
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Rotunno
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Saul
authors.initials: S
authors.lastname: Penaranda
authors.affiliation: Marine Biological Laboratory, Woods Hole, MA, USA.
authors.forename: Izrail
authors.initials: I
authors.lastname: Abdurakhmanov
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Landers
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA. gmorfini@uic.edu.|Marine Biological Laboratory, Woods Hole, MA, USA. gmorfini@uic.edu.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Morfini
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA. stbrady@uic.edu.|Marine Biological Laboratory, Woods Hole, MA, USA. stbrady@uic.edu.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Brady
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA. Daryl.Bosco@umassmed.edu.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Bosco
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D049832:Decapodiformes / Q000254:growth & development / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D017510:Protein Folding; D034702:RNA-Binding Protein FUS / Q000737:chemistry / Q000235:genetics*; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C000599550:FUS protein, human; D034702:RNA-Binding Protein FUS; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1; D048051:p38 Mitogen-Activated Protein Kinases