Human Molecular Genetics

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Human Molecular Genetics, 2000, Vol. 9, No. 19 2799-2809
© 2000 Oxford University Press

Dominant phenotypes produced by the HD mutation in STHdh^Q111 striatal cells

Flavia Trettel, Dorotea Rigamonti¹, Paige Hilditch-Maguire, Vanessa C. Wheeler, Alan H. Sharp², Francesca Persichetti, Elena Cattaneo¹ and Marcy E. MacDonald⁺

Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA, ¹Institute of Pharmacological Sciences, University of Milano, 20133 Milano, Italy and ²Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington’s disease (HD). To identify pathways that are candidates for the mutant protein’s abnormal function, we compared striatal cell lines established from wild-type and Hdh^Q111 knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh^Q111 cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.

⁺ To whom correspondence should be addressed: Tel: +1 617 726 5089; Fax: +1 617 726 5735; Email: macdonam@helix.mgh.harvard.edu

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