Journal Article

Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in <i>Hdh</i> CAG knock-in mice

Vanessa C. Wheeler, Claire-Anne Gutekunst, Vladimir Vrbanac, Lori-Anne Lebel, Gabriele Schilling, Steven Hersch, Robert M. Friedlander, James F. Gusella, Jean-Paul Vonsattel, David R. Borchelt and Marcy E. MacDonald

in Human Molecular Genetics

Volume 11, issue 6, pages 633-640
Published in print March 2002 | ISSN: 0964-6906
Published online March 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.6.633
Early phenotypes that presage late-onset neurodegenerative disease allow testing of modifiers in Hdh CAG knock-in mice

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In Huntington’s disease (HD), CAG repeats extend a glutamine tract in huntingtin to initiate the dominant loss of striatal neurons and chorea. Neuropathological changes include the formation of insoluble mutant N-terminal fragment, as nuclear/neuropil inclusions and filter-trap amyloid, which may either participate in the disease process or be a degradative by-product. In young Hdh knock-in mice, CAGs that expand the glutamine tract in mouse huntingtin to childhood-onset HD lengths lead to nuclear accumulation of full-length mutant huntingtin and later accumulation of insoluble fragment. Here we report late-onset neurodegeneration and gait deficits in older HdhQ111 knock-in mice, demonstrating that the nuclear phenotypes comprise early stages in a disease process that conforms to genetic and pathologic criteria determined in HD patients. Furthermore, using the early nuclear-accumulation phenotypes as surrogate markers, we show in genetic experiments that the disease process, initiated by full-length mutant protein, is hastened by co-expression of mutant fragment; therefore, accrual of insoluble-product in already compromised neurons may exacerbate pathogenesis. In contrast, timing of early disease events was not altered by normal huntingtin or by mutant caspase-1, two proteins shown to reduce inclusions and glutamine toxicity in other HD models. Thus, potential HD therapies in man might be directed at different levels: preventing the disease-initiating mechanism or slowing the subsequent progression of pathogenesis.

Journal Article.  5185 words.  Illustrated.

Subjects: Genetics and Genomics

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