Activity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasis

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dc.contributor.ISNI0000 0001 1707 1372 (Zhang, MQ)
dc.contributor.LCNA99086074‏ (Zhang, MQ)en_US
dc.contributor.authorSephton, Chantelle F.en_US
dc.contributor.authorTang, Amy A.en_US
dc.contributor.authorKulkarni, Ashwinikumaren_US
dc.contributor.authorWest, Jamesen_US
dc.contributor.authorBrooks, Mieuen_US
dc.contributor.authorStubblefield, Jeremy J.en_US
dc.contributor.authorLiu, Yunen_US
dc.contributor.authorZhang, Michael Q.en_US
dc.contributor.authorGreen, Carla B.en_US
dc.contributor.authorHuber, Kimberly M.en_US
dc.contributor.authorHuang, Eric J.en_US
dc.contributor.authorHerz, Joachimen_US
dc.contributor.authorYu, Gangen_US
dc.contributor.utdAuthorZhang, Michael Q.en_US
dc.date.accessioned2014-12-19T17:20:28Z
dc.date.available2014-12-19T17:20:28Z
dc.date.created2014-10-16en_US
dc.date.issued2014-10-16en_US
dc.descriptionThis article contains supporting information online at: http://www.pnas.org/content/111/44/E4769/suppl/DCSupplementalen_US
dc.description.abstractThe RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUSWT) and a pathological mutation (FUSR521G). FUSWT and FUSR521G mice that develop severe motor deficits also show neuroinflammation, denervated neuromuscular junctions, and premature death, phenocopying the human diseases. A portion of FUSR521G mice escape early lethality; these escapers have modest motor impairments and altered sociability, which correspond with a reduction of dendritic arbors and mature spines. Remarkably, only FUSR521G mice show dendritic defects; FUSWT mice do not. Activation of metabotropic glutamate receptors 1/5 in neocortical slices and isolated synaptoneurosomes increases endogenous mouse FUS and FUSWT protein levels but decreases the FUSR521G protein, providing a potential biochemical basis for the dendritic spine differences between FUSWT and FUSR521G mice.en_US
dc.identifier.bibliographicCitationSephton, Chantelle F., Amy A. Tang, Ashwinikumar Kulkarni, James West, et al. 2014. "Activity-dependent FUS dysregulation disrupts synaptic homeostasis." Proceedings of the National Academy of Sciences of the United States of America 111(44): E4769-E4778.en_US
dc.identifier.issn0027-8424en_US
dc.identifier.issue44en_US
dc.identifier.urihttp://hdl.handle.net/10735.1/4236
dc.identifier.volume111en_US
dc.language.isoenen_US
dc.publisherNatl Acad Sciencesen_US
dc.relation.urihttp://dx.doi.org/10.1073/pnas.1406162111
dc.rights©2014 The Authors. "Freely available online through the PNAS open access option."en_US
dc.sourceProceedings of the National Academy of Sciences of the United States of America
dc.subjectFUS proteinen_US
dc.subjectAmyotrophic Lateral Sclerosisen_US
dc.subjectFrontotemporal Lobar Degenerationen_US
dc.subjectMotor neuronsen_US
dc.subjectRNAen_US
dc.titleActivity-Dependent FUS Dysregulation Disrupts Synaptic Homeostasisen_US
dc.type.genreArticleen_US

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Zhang, Michael Q.
NSM Staff-Student Research