Journal Article

Dominant phenotypes produced by the <i>HD</i> mutation in ST<i>Hdh</i><i><sup>Q111</sup></i> striatal cells

Flavia Trettel, Dorotea Rigamonti, Paige Hilditch-Maguire, Vanessa C. Wheeler, Alan H. Sharp, Francesca Persichetti, Elena Cattaneo and Marcy E. MacDonald

in Human Molecular Genetics

Volume 9, issue 19, pages 2799-2809
Published in print November 2000 | ISSN: 0964-6906
Published online November 2000 | e-ISSN: 1460-2083 | DOI:
Dominant phenotypes produced by the HD mutation in STHdhQ111 striatal cells

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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 HdhQ111 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 STHdhQ111 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.

Journal Article.  7003 words.  Illustrated.

Subjects: Genetics and Genomics

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