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dc.contributor.authorYu, M
dc.contributor.authorFu, Y
dc.contributor.authorLiang, Y
dc.contributor.authorSong, H
dc.contributor.authorYao, Y
dc.contributor.authorWu, P
dc.contributor.authorYao, Y
dc.contributor.authorPan, Y
dc.contributor.authorWen, X
dc.contributor.authorMa, L
dc.contributor.authorHexige, S
dc.contributor.authorDing, Y
dc.contributor.authorLuo, S
dc.contributor.authorLu, B
dc.date.accessioned2018-03-20T09:13:03Z
dc.date.available2018-03-20T09:13:03Z
dc.date.issued2017-12
dc.identifier.issn1001-0602
dc.identifier.issn1748-7838
dc.identifier.urihttp://hdl.handle.net/10026.1/11108
dc.description.abstract

Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases.

dc.format.extent1441-1465
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.subjectPolyQ
dc.subjecthigh-throughput screening
dc.subjectprotein homeostasis
dc.subjectkinase
dc.subjectpositive feedback mechanism
dc.subjectneurodegenerative disorders
dc.titleSuppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models
dc.typejournal-article
dc.typeArticle
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/29151587
plymouth.issue12
plymouth.volume27
plymouth.publication-statusPublished
plymouth.journalCell Research
dc.identifier.doi10.1038/cr.2017.113
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Research Groups
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)
plymouth.organisational-group/Plymouth/Research Groups/Institute of Translational and Stratified Medicine (ITSMED)/CBR
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
plymouth.organisational-group/Plymouth/Users by role/Researchers in ResearchFish submission
dc.publisher.placeEngland
dcterms.dateAccepted2017-08-08
dc.identifier.eissn1748-7838
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1038/cr.2017.113
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-12
rioxxterms.typeJournal Article/Review
plymouth.funderTackling autophagy and apoptosis for the potential therapy of Huntington's Disease::MRC


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