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dc.contributor.authorSama, Reddy Ranjith K.  Concept link
dc.contributor.authorFallini, Claudia  Concept link
dc.contributor.authorGatto, Rodolfo  Concept link
dc.contributor.authorMcKeon, Jeanne E.  Concept link
dc.contributor.authorSong, Yuyu  Concept link
dc.contributor.authorRotunno, Melissa S.  Concept link
dc.contributor.authorPenaranda, Saul  Concept link
dc.contributor.authorAbdurakhmanov, Izrail  Concept link
dc.contributor.authorLanders, John E.  Concept link
dc.contributor.authorMorfini, Gerardo A.  Concept link
dc.contributor.authorBrady, Scott T.  Concept link
dc.contributor.authorBosco, Daryl A.  Concept link
dc.identifier.citationScientific Reports 7 (2017): 115en_US
dc.description© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 115, doi:10.1038/s41598-017-00091-1.en_US
dc.description.abstractMutations 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.en_US
dc.description.sponsorshipWe are grateful for funding from NIH/NINDS (R01 NS078145, R01 NS090352, and R21 NS091860 to D.A.B., R01 NS066942A and R21 NS096642 to G.M., R01NS023868 and R01NS041170 to S.T.B.), the ALS Therapy Alliance/CVS Pharmacy (to D.A.B. and G.M.) and the ALS Association (to C.F. and J.M.).en_US
dc.publisherNature Publishing Groupen_US
dc.rightsAttribution 4.0 International*
dc.titleALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activationen_US

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Except where otherwise noted, this item's license is described as Attribution 4.0 International