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dc.contributor.authorSama, Reddy Ranjith Kumar
dc.contributor.authorFallini, Claudia
dc.contributor.authorGatto, Rodolfo
dc.contributor.authorMcKeon, Jeanne E.
dc.contributor.authorSong, Yuyu
dc.contributor.authorRotunno, Melissa S.
dc.contributor.authorPenaranda, Saul
dc.contributor.authorAbdurakhmanov, Izrail
dc.contributor.authorLanders, John E.
dc.contributor.authorMorfini, Gerardo
dc.contributor.authorBrady, Scott T.
dc.contributor.authorBosco, Daryl
dc.date2022-08-11T08:09:47.000
dc.date.accessioned2022-08-23T16:43:33Z
dc.date.available2022-08-23T16:43:33Z
dc.date.issued2017-03-08
dc.date.submitted2017-09-15
dc.identifier.citationSci Rep. 2017 Mar 8;7(1):115. doi: 10.1038/s41598-017-00091-1. <a href="https://doi.org/10.1038/s41598-017-00091-1">Link to article on publisher's site</a>
dc.identifier.issn2045-2322 (Linking)
dc.identifier.doi10.1038/s41598-017-00091-1
dc.identifier.pmid28273913
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40317
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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=28273913&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright © The Author(s) 2017
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectAmyotrophic lateral sclerosis
dc.subjectKinases
dc.subjectMechanisms of disease
dc.subjectMotor proteins
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectNervous System Diseases
dc.subjectNeurology
dc.subjectNeuroscience and Neurobiology
dc.titleALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
dc.typeJournal Article
dc.source.journaltitleScientific reports
dc.source.volume7
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=4125&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/3118
dc.identifier.contextkey10750059
refterms.dateFOA2022-08-23T16:43:33Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathoapubs/3118
dc.contributor.departmentDepartment of Neurology
dc.source.pages115


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