Home >> Human Molecular Genetics, Volume 9, Number 4

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

Authors: Wheeler, Vanessa C.1; White, Jacqueline K.1; Gutekunst, Claire-Anne2; Vrbanac, Vladimir1; Weaver, Meredith1; Li, Xiao-Jiang3; Li, Shi-Hua3; Yi, Hong2; Vonsattel, Jean-Paul4; Gusella, James F.1; Hersch, Steven2; Auerbach, Wojtek5; Joyner, Alexandra L.5; MacDonald, Marcy E.1

Source: Human Molecular Genetics, Volume 9, Number 4, 1 March 2000 , pp. 503-513(11)

Publisher: Oxford University Press

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Abstract:

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.

Document Type: Research article

Affiliations: 1: Molecular Neurogenetics Unit, 2: Department of Neurology, 3: Department of Genetics and Molecular Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA, 4: Laboratory for Molecular Neuropathology Massachusetts General Hospital, Charlestown, MA 02129, USA, 5: Howard Hughes Medical Institute and Skirball Institute for Biomolecular Medicine and

Publication date: 2000-03-01

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