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 for...

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Autores principales:	Reddy Ranjith K. Sama, Claudia Fallini, Rodolfo Gatto, Jeanne E. McKeon, Yuyu Song, Melissa S. Rotunno, Saul Penaranda, Izrail Abdurakhmanov, John E. Landers, Gerardo Morfini, Scott T. Brady, Daryl A. Bosco
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f67025a8d9b84438822ee997bac6b02a
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spelling	oai:doaj.org-article:f67025a8d9b84438822ee997bac6b02a2021-12-02T11:52:42ZALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation10.1038/s41598-017-00091-12045-2322https://doaj.org/article/f67025a8d9b84438822ee997bac6b02a2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00091-1https://doaj.org/toc/2045-2322Abstract 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.Reddy Ranjith K. SamaClaudia FalliniRodolfo GattoJeanne E. McKeonYuyu SongMelissa S. RotunnoSaul PenarandaIzrail AbdurakhmanovJohn E. LandersGerardo MorfiniScott T. BradyDaryl A. BoscoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Reddy Ranjith K. Sama Claudia Fallini Rodolfo Gatto Jeanne E. McKeon Yuyu Song Melissa S. Rotunno Saul Penaranda Izrail Abdurakhmanov John E. Landers Gerardo Morfini Scott T. Brady Daryl A. Bosco ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
description	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.
format	article
author	Reddy Ranjith K. Sama Claudia Fallini Rodolfo Gatto Jeanne E. McKeon Yuyu Song Melissa S. Rotunno Saul Penaranda Izrail Abdurakhmanov John E. Landers Gerardo Morfini Scott T. Brady Daryl A. Bosco
author_facet	Reddy Ranjith K. Sama Claudia Fallini Rodolfo Gatto Jeanne E. McKeon Yuyu Song Melissa S. Rotunno Saul Penaranda Izrail Abdurakhmanov John E. Landers Gerardo Morfini Scott T. Brady Daryl A. Bosco
author_sort	Reddy Ranjith K. Sama
title	ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
title_short	ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
title_full	ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
title_fullStr	ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
title_full_unstemmed	ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
title_sort	als-linked fus exerts a gain of toxic function involving aberrant p38 mapk activation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f67025a8d9b84438822ee997bac6b02a
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ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation

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