Journal Article

Truncated N-Terminal Fragments of Huntingtin with Expanded Glutamine Repeats form Nuclear and Cytoplasmic Aggregates in Cell Culture

Jillian K. Cooper, Gabriele Schilling, Matthew F. Peters, William J. Herring, Alan H. Sharp, Zachary Kaminsky, Jamie Masone, Farhat A. Khan, Michael Delanoy, David R. Borchelt, Valina L. Dawson, Ted M. Dawson and Christopher A. Ross

in Human Molecular Genetics

Volume 7, issue 5, pages 783-790
Published in print May 1998 | ISSN: 0964-6906
Published online May 1998 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/7.5.783
Truncated N-Terminal Fragments of Huntingtin with Expanded Glutamine Repeats form Nuclear and Cytoplasmic Aggregates in Cell Culture

Show Summary Details

Preview

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanding CAG repeat coding for polyglutamine in the huntingtin protein. Recent data have suggested the possibility that an N-terminal fragment of huntingtin may aggregate in neurons of patients with HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus, forming intranuclear neuronal inclusion bodies. An animal model of HD using the short N-terminal fragment of huntingtin has also been found to have intranuclear inclusions and this same fragment can aggregate in vitro. We have now developed a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus. Neuroblastoma cells transiently transfected with full-length huntingtin constructs with either a normal or expanded repeat had diffuse cytoplasmic localization of the protein. In contrast, cells transfected with truncated N-terminal fragments showed aggregation only if the glutamine repeat was expanded. The aggregates were often ubiquitinated. The shorter truncated product appeared to form more aggregates in the nucleus. Cells transfected with the expanded repeat construct but not the normal repeat construct showed enhanced toxicity to the apoptosis-inducing agent staurosporine. These data indicate that N-terminal truncated fragments of huntingtin with expanded glutamine repeats can aggregate in cells in culture and that this aggregation can be toxic to cells. This model will be useful for future experiments to test mechanisms of aggregation and toxicity and potentially for testing experimental therapeutic interventions.

Journal Article.  5399 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.