{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/113947"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/113947","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Modulation of Huntington's disease-associated phenotypes by the striatal-enriched transcription factor Foxp2","abstract":"Huntington's disease (HD), the most common inherited neurodegenerative disorder, is caused by mutations in the huntingtin (HTT) gene, which encodes a poly-glutamine (polyQ) repeat protein. Despite widespread expression of the HTT gene, HD presents with massive neuronal cell loss and transcriptional dysregulation primarily in the striatum and deep layers of the cortex. Synaptic dysfunction and motor deficits are also prominent in HD patients as well as mouse models. In an attempt to identify factors that could both explain these alterations and mirror these vulnerability patterns, we identified a potential role for the striatal-enriched polyQ protein Foxp2 in HD. The transcription factor Foxp2 was recently identified as a crucial regulator of striatal synaptogenesis and corticostriatal inputs during striatal development, and has also been demonstrated to play a critical role in motor learning. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type adult striatum leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant HTT protein. Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD.","abstract_html":"Huntington's disease (HD), the most common inherited neurodegenerative disorder, is caused by mutations in the huntingtin (HTT) gene, which encodes a poly-glutamine (polyQ) repeat protein. Despite widespread expression of the HTT gene, HD presents with massive neuronal cell loss and transcriptional dysregulation primarily in the striatum and deep layers of the cortex. Synaptic dysfunction and motor deficits are also prominent in HD patients as well as mouse models. In an attempt to identify factors that could both explain these alterations and mirror these vulnerability patterns, we identified a potential role for the striatal-enriched polyQ protein Foxp2 in HD. The transcription factor Foxp2 was recently identified as a crucial regulator of striatal synaptogenesis and corticostriatal inputs during striatal development, and has also been demonstrated to play a critical role in motor learning. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type adult striatum leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant HTT protein. Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD.","abstract_has_math":false,"creators":["Hachigian, Lea June"],"institution":"Massachusetts Institute of Technology","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences.","school":null,"contributors":[],"advisors":["Myriam Heiman."],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017","date_published":"2017","updated_at":"2026-07-22T22:21:20Z","subjects":["Brain and Cognitive Sciences."],"languages":["eng"],"rights":["MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission."],"rights_urls":["http://dspace.mit.edu/handle/1721.1/7582"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1721.1/113947","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Myriam Heiman."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Massachusetts Institute of Technology. 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Despite widespread expression of the HTT gene, HD presents with massive neuronal cell loss and transcriptional dysregulation primarily in the striatum and deep layers of the cortex. Synaptic dysfunction and motor deficits are also prominent in HD patients as well as mouse models. In an attempt to identify factors that could both explain these alterations and mirror these vulnerability patterns, we identified a potential role for the striatal-enriched polyQ protein Foxp2 in HD. The transcription factor Foxp2 was recently identified as a crucial regulator of striatal synaptogenesis and corticostriatal inputs during striatal development, and has also been demonstrated to play a critical role in motor learning. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type adult striatum leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant HTT protein. Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes which present new targets for normalization of corticostriatal dysfunction in HD."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph. D."]},{"key":"dc:title","label":"Title","values":["Modulation of Huntington's disease-associated phenotypes by the striatal-enriched transcription factor Foxp2"]}]}],"canonical_facts":{"dc:contributor.advisor":["Myriam Heiman."],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences."],"dc:contributor.other":["Massachusetts Institute of Technology. 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In an attempt to identify factors that could both explain these alterations and mirror these vulnerability patterns, we identified a potential role for the striatal-enriched polyQ protein Foxp2 in HD. The transcription factor Foxp2 was recently identified as a crucial regulator of striatal synaptogenesis and corticostriatal inputs during striatal development, and has also been demonstrated to play a critical role in motor learning. Here we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type adult striatum leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant HTT protein. 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