Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice

VC Wheeler, JK White, CA Gutekunst… - Human molecular …, 2000 - academic.oup.com
VC Wheeler, JK White, CA Gutekunst, V Vrbanac, M Weaver, XJ Li, SH Li, H Yi, JP Vonsattel…
Human molecular genetics, 2000academic.oup.com
Huntington's disease (HD) is caused by an expanded N-terminal glutamine tract that
endows huntingtin with a striatal-selective structural property ultimately toxic to medium
spiny neurons. In precise genetic models of juvenile HD, Hdh Q92 and Hdh Q111 knock-in
mice, long polyglutamine segments change huntingtin's physical properties, producing HD-
like in vivo correlates in the striatum, including nuclear localization of a version of the full-
length protein predominant in medium spiny neurons, and subsequent formation of N …
Huntington’s disease (HD) is caused by an expanded N-terminal glutamine tract that endows huntingtin with a striatal-selective structural property ultimately toxic to medium spiny neurons. In precise genetic models of juvenile HD, HdhQ92 and HdhQ111 knock-in mice, long polyglutamine segments change huntingtin’s physical properties, producing HD-like in vivo correlates in the striatum, including nuclear localization of a version of the full-length protein predominant in medium spiny neurons, and subsequent formation of N-terminal inclusions and insoluble aggregate. These changes show glutamine length dependence and dominant inheritance with recruitment of wild-type protein, critical features of the altered HD property that strongly implicate them in the HD disease process and that suggest alternative pathogenic scenarios: the effect of the glutamine tract may act by altering interaction with a critical cellular constituent or by depleting a form of huntingtin essential to medium spiny striatal neurons.
Oxford University Press