About this item:

469 Views | 71 Downloads

Author Notes:

To whom correspondence should be addressed: Dept. of Human Genetics, Emory University School of Medicine, 615 Michael St., Atlanta, GA 30322. Tel.: 404-727-3290; Fax: 404-727-3949; E-mail: xli2@emory.edu.

Both authors contributed equally to this work.

Subjects:

Research Funding:

This work was supported, in whole or in part, by National Institutes of Health Grants NS36232 (to X.-J. L.), AG19206 (to X.-J. L.), AG031153 (to S. H. L.), and NS045016 (to S. H. L.).

Keywords:

  • Aging
  • Diseases/Aging
  • Diseases/Genetic
  • Diseases/Neurodegeneration
  • Diseases/Neurological
  • Gene/Transcription

Mutant Huntingtin in Glial Cells Exacerbates Neurological Symptoms of Huntington Disease Mice

Tools:

Journal Title:

Journal of Biological Chemistry

Volume:

Volume 285, Number 14

Publisher:

, Pages 10653-10661

Type of Work:

Article | Final Publisher PDF

Abstract:

Huntington disease (HD) is caused by an expansion of the polyglutamine (polyQ) repeat (>37Q) in huntingtin (htt), and age of onset is inversely correlated with the length of the polyQ repeat. Mutant htt with expanded polyQ is ubiquitously expressed in various types of cells, including glia, but causes selective neurodegeneration. Our recent study demonstrated that expression of the N-terminal mutant htt with a large polyQ repeat (160Q) in astrocytes is sufficient to induce neurological symptoms in mice (Bradford, J., Shin, J. Y., Roberts, M., Wang, C. E., Li, X.-J., and Li, S. H. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 22480–22485). Because glia-neuron interactions are critical for maintaining the normal function and survival of neurons in the brain and because mutant htt is more abundant in neurons than in glial cells, it is important to investigate whether glial htt can still contribute to HD pathology when mutant htt is abundantly expressed in neuronal cells. We generated transgenic mice that express mutant htt with 98Q in astrocytes. Unlike our recently generated htt-160Q transgenic mice, htt-98Q mice do not show obvious neurological phenotypes, suggesting that the length of the polyQ repeat determines the severity of glial dysfunction. However, htt-98Q mice show increased susceptibility to glutamate-induced seizure. Mice expressing mutant htt in astrocytes were mated with N171-82Q mice that express mutant htt primarily in neuronal cells. Double transgenic mice expressing mutant htt in both neuronal and glial cells display more severe neurological symptoms and earlier death than N171-82Q mice. These findings indicate a role of glial mutant htt in exacerbating HD neuropathology and underscore the importance of improving glial function in treating HD.

Copyright information:

© 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Export to EndNote