Modulation of Huntington's disease-associated phenotypes by the striatal-enriched transcription factor Foxp2
Author(s)Hachigian, Lea June
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences.
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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.
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Brain and Cognitive Sciences, 2017.Cataloged from PDF version of thesis.Includes bibliographical references (pages 158-177).
DepartmentMassachusetts Institute of Technology. Department of Brain and Cognitive Sciences.
Massachusetts Institute of Technology
Brain and Cognitive Sciences.