Journal Article

Intranuclear Inclusions and Neuritic Aggregates in Transgenic Mice Expressing a Mutant N-Terminal Fragment of Huntingtin

Gabriele Schilling, Mark W. Becher, Alan H. Sharp, Hyder A. Jinnah, Kui Duan, Joyce A. Kotzuk, Hilda H. Slunt, Tamara Ratovitski, Jillian K. Cooper, Nancy A. Jenkins, Neal G. Copeland, Donald L. Price, Christopher A. Ross and David R. Borchelt

in Human Molecular Genetics

Volume 8, issue 3, pages 397-407
Published in print March 1999 | ISSN: 0964-6906
Published online March 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.3.397
Intranuclear Inclusions and Neuritic Aggregates in Transgenic Mice Expressing a Mutant N-Terminal Fragment of Huntingtin

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Huntington's disease (HD) is an inherited, neurodegenerative disorder caused by the expansion of a glutamine repeat in the N-terminus of the huntingtin protein. To gain insight into the pathogenesis of HD, we generated transgenic mice that express a cDNA encoding an N-terminal fragment (171 amino acids) of huntingtin with 82, 44 or 18 glutamines. Mice expressing relatively low steady-state levels of N171 huntingtin with 82 glutamine repeats (N171-82Q) develop behavioral abnormalities, including loss of coordination, tremors, hypokinesis and abnormal gait, before dying prematurely. In mice exhibiting these abnormalities, diffuse nuclear labeling, intranuclear inclusions and neuritic aggregates, all immunoreactive with an antibody to the N-terminus (amino acids 1–17) of huntingtin (AP194), were found in multiple populations of neurons. None of these behavioral or pathological phenotypes were seen in mice expressing N171-18Q. These findings are consistent with the idea that N-terminal fragments of huntingtin with a repeat expansion are toxic to neurons, and that N-terminal fragments are prone to form both intranuclear inclusions and neuritic aggregates.

Journal Article.  6691 words.  Illustrated.

Subjects: Genetics and Genomics

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