Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in Hdh(Q92) and Hdh(Q111) knock-in mice

Huntington's disease (HD) is caused by an expanded N-terminal glutamine tra ct that endows huntingtin with a striatal-selective structural property ult imately toxic to medium spiny neurons. In precise genetic models of juvenil e HD, Hdh(Q92) and Hdh(Q111) knock-in mice, long polyglutamine segments cha nge huntingtin's physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-le ngth protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutam ine length dependence and dominant inheritance with recruitment of wild-typ e protein, critical features of the altered HD property that strongly impli cate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interacti on with a critical cellular constituent or by depleting a form of huntingti n essential to medium spiny striatal neurons.