Generation and Characterization of Knock-in Mouse Models Expressing Versions of Normal (7Q) and Mutant (140Q) Huntington with Deletions of the Proline-rich Region

Huntington's disease (HD) is an autosomal dominant disorder that is caused by the expansion of a polyglutamine (polyQ) tract in the huntingtin (htt) protein. HD is one of several neurodegenerative diseases that are caused by an expansion of a polyQ stretch in a ubiquitously expressed protein. The htt polyQ stretch is flanked by two evolutionarily conserved domains–an amino terminal N17 domain, and a proline-rich region (PRR). The overall goal of my research is to understand how the PRR contributes to wild-type htt function, and can modulate mutant htt pathogenesis in vivo. To determine the role of the PRR in normal htt function, I characterized a knock-in mouse line expressing a version of the mouse HD gene that contains a deletion of its PRR in the context of the normal murine 7Q stretch (Hdh ∆P ). I was able to obtain mice homozygous for this deletion (Hdh ∆P/∆P ), suggesting that the PRR is not required for htt's normal essential functions during development. In older Hdh ∆P/∆P mice, I observed only a mild behavioral phenotype, a result suggesting that the deletion of the PRR in the context of a normal polyQ stretch has only a subtle impact on htt function in the adult brain. To determine the role of the PRR in modulating the toxic effects of htt's expanded polyQ stretch, I generated a knock-in mouse model expressing a version of htt with both an expanded stretch of polyQ (140Q) and a deletion of the adjacent PRR (Hdh 140Q-∆P ). I observed a change in the conformation of mutant htt aggregates, an alteration in their subcellular localization, and a reduction in mutant aggregate numbers in Hdh 140Q-∆P/+ mice compared to Hdh 140Q/+ mice. In addition, behavioral deficits in Hdh 140Q-∆P/+ mice were ameliorated in comparison to the Hdh 140Q/+ mice. Taken together, my data suggest III that the deletion of the htt PRR in the context of a normal polyQ stretch has only a minimal effect on htt function, while a PRR deletion in the context of an expanded polyQ stretch can modulate mutant htt toxicity by altering the kinetics of mutant htt aggregate formation and their conformation.

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