Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease

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dc.contributor.authorTitus, Anto Sam Crosslee Louis Samen_US
dc.contributor.authorYusuff, Tanzeenen_US
dc.contributor.authorCassar, Marleneen_US
dc.contributor.authorThomas, Elizabethen_US
dc.contributor.authorKretzschmar, Dorisen_US
dc.contributor.authorD'Mello, Santosh R.en_US
dc.contributor.utdAuthorTitus, Anto Sam Crosslee Louis Samen_US
dc.contributor.utdAuthorD'Mello, Santosh R.en_US
dc.date.accessioned2018-09-24T15:56:42Z
dc.date.available2018-09-24T15:56:42Z
dc.date.created2017-07-05
dc.date.issued2017-07-05en_US
dc.description.abstractHuntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntington protein (het). The neuropathological hallmark of HD is the loss of neurons in the striatum and, to a lesser extent, in the cortex. Foxp1 is a member of the Forkhead family of transcription factors expressed selectively in the striatum and the cortex. In the brain, three major Foxp1 isoforms are expressed: isoform-A (similar to 90 kDa), isoform-D (similar to 70 kDa), and isoform-C (similar to 50 kDa). We find that expression of Foxp1 isoform-A and -D is selectively reduced in the striatum and cortex of R6/2 HD mice as well as in the striatum of HD patients. Furthermore, expression of mutant htt in neurons results in the downregulation of Foxp1. Elevating expression of isoform-A or -D protects cortical neurons from death caused by the expression of mutant hit. On the other hand, knockdown of Foxp1 promotes death in otherwise healthy neurons. Neuroprotection by Foxp1 is likely to be mediated by the transcriptional stimulation of the cell-cycle inhibitory protein p21^{Waf1/Cip1}. Consistently, Foxp1 activates transcription of the p21^{Waf1/Cip1} gene promoter, and overexpression of Foxp1 in neurons results in the elevation of p21 expression. Moreover, knocking down of p21^{Waf1/Cip1} blocks the ability of Foxp1 to protect neurons from mut-Htt-induced neurotoxicity. We propose that the selective vulnerability of neurons of the striatum and cortex in HD is related to the loss of expression of Foxp1, a protein that is highly expressed in these neurons and required for their survival.en_US
dc.description.departmentSchool of Natural Sciences and Mathematicsen_US
dc.description.sponsorshipNIH Grant NS040408en_US
dc.identifier.bibliographicCitationTitus, Anto Sam Crosslee Louis Sam, Tanzeen Yusuff, Marlene Cassar, Elizabeth Thomas, et al. 2017. "Reduced Expression of Foxp1 as a Contributing Factor in Huntington's Disease." Journal of Neuroscience 37(27): 6575-6587.en_US
dc.identifier.issn0270-6474en_US
dc.identifier.issue27en_US
dc.identifier.urihttp://hdl.handle.net/10735.1/6138
dc.identifier.volume37en_US
dc.language.isoenen_US
dc.publisherSoc Neuroscienceen_US
dc.relation.urihttp://dx.doi.org/10.1523/JNEUROSCI.3612-16.2017
dc.rightsCC BY 4.0 (Attribution)en_US
dc.rights©2017 The Authorsen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.sourceJournal of Neuroscience
dc.subjectFOXP1 proteinen_US
dc.subjectGene Expressionen_US
dc.subjectIntellectual Disabilityen_US
dc.subjectEuropean Continental Ancestry Groupen_US
dc.subjectNeuronsen_US
dc.subjectCell Deathen_US
dc.subjectDrosophilaen_US
dc.subjectToxicity Testsen_US
dc.subjectBrainen_US
dc.subjectHuntington Diseaseen_US
dc.subjectNerve Degenerationen_US
dc.subjectNeuroprotectionen_US
dc.titleReduced Expression of Foxp1 as a Contributing Factor in Huntington's Diseaseen_US
dc.type.genrearticleen_US

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