Absence of Behavioral Abnormalities and Neurodegeneration in vivo despite Widespread Neuronal Huntingtin Inclusions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 32; pp. 11402 - 11407
• Main Authors: Slow, Elizabeth J., Graham, Rona K., Osmand, Alexander P., Devon, Rebecca S., Lu, Ge, Deng, Yu, Pearson, Jacqui, Vaid, Kuljeet, Bissada, Nagat, Wetzel, Ronald, Leavitt, Blair R., Hayden, Michael R., Palmiter, Richard D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 09.08.2005; National Acad Sciences
• Subjects: Analysis of Variance; Animals; Antibodies; Behavioral Symptoms - genetics; Behavioral Symptoms - physiopathology; Biological Sciences; Brain; Brain - pathology; Chromosomes, Artificial, Yeast - genetics; Computational Biology; Disease Models, Animal; DNA Primers; Gene expression; Hippocampus; Humans; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - pathology; Huntington Disease - physiopathology; Inclusion bodies; Inclusion Bodies - genetics; Inclusion Bodies - pathology; Introns; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - physiology; Neurological disorders; Neurons; Neurons - pathology; Neurons - physiology; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Phenotypes; Polymerase chain reaction; Promoter Regions, Genetic - genetics; Proteins; Rodents; Rotarod Performance Test; Sequence Analysis, DNA; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0503634102

We have serendipitously established a mouse that expresses an N-terminal human huntingtin (htt) fragment with an expanded polyglutamine repeat (≈120) under the control of the endogenous human promoter (shortstop). Frequent and widespread htt inclusions occur early in shortstop mice. Despite these inclusions, shortstop mice display no clinical evidence of neuronal dysfunction and no neuronal degeneration as determined by brain weight, striatal volume, and striatal neuronal count. These results indicate that htt inclusions are not pathogenic in vivo. In contrast, the full-length yeast artificial chromosome (YAC) 128 model with the identical polyglutamine length and same level of transgenic protein expression as the shortstop demonstrates significant neuronal dysfunction and loss. In contrast to the YAC128 mouse, which demonstrates enhanced susceptibility to excitotoxic death, the shortstop mouse is protected from excitotoxicity, providing in vivo evidence suggesting that neurodegeneration in Huntington disease is mediated by excitotoxic mechanisms.