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The Journal of Neuroscience, June 11, 2008, 28(24):6182-6195; doi:10.1523/JNEUROSCI.0857-08.2008

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Neurobiology of Disease
Full-Length Human Mutant Huntingtin with a Stable Polyglutamine Repeat Can Elicit Progressive and Selective Neuropathogenesis in BACHD Mice

Michelle Gray,^1,3,4 Dyna I. Shirasaki,^1,6 Carlos Cepeda,^2,3,4 Véronique M. André,^2,3,4 Brian Wilburn,^1,3,4 Xiao-Hong Lu,^1,3,4 Jifang Tao,⁵ Irene Yamazaki,^2,3,4 Shi-Hua Li,⁷ Yi E. Sun,^2,3,4,5 Xiao-Jiang Li,⁷ Michael S. Levine,^2,3,4 and X. William Yang^1,3,4

¹Center for Neurobehavioral Genetics, ²Mental Retardation Research Center, Semel Institute for Neuroscience and Human Behavior, ³Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, ⁴David Geffen School of Medicine, ⁵Departments of Molecular and Medical Pharmacology and ⁶Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, and ⁷Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322

Correspondence should be addressed to X. William Yang, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive, 3524 Gonda, Los Angeles, CA 90095. Email: xwyang{at}mednet.ucla.edu

To elucidate the pathogenic mechanisms in Huntington's disease (HD) elicited by expression of full-length human mutant huntingtin (fl-mhtt), a bacterial artificial chromosome (BAC)-mediated transgenic mouse model (BACHD) was developed expressing fl-mhtt with 97 glutamine repeats under the control of endogenous htt regulatory machinery on the BAC. BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and late-onset selective neuropathology, which includes significant cortical and striatal atrophy and striatal dark neuron degeneration. Power analyses reveal the robustness of the behavioral and neuropathological phenotypes, suggesting BACHD as a suitable fl-mhtt mouse model for preclinical studies. Additional analyses of BACHD mice provide novel insights into how mhtt may elicit neuropathogenesis. First, unlike previous fl-mhtt mouse models, BACHD mice reveal that the slowly progressive and selective pathogenic process in HD mouse brains can occur without early and diffuse nuclear accumulation of aggregated mhtt (i.e., as detected by immunostaining with the EM48 antibody). Instead, a relatively steady-state level of predominantly full-length mhtt and a small amount of mhtt N-terminal fragments are sufficient to elicit the disease process. Second, the polyglutamine repeat within fl-mhtt in BACHD mice is encoded by a mixed CAA-CAG repeat, which is stable in both the germline and somatic tissues including the cortex and striatum at the onset of neuropathology. Therefore, our results suggest that somatic repeat instability does not play a necessary role in selective neuropathogenesis in BACHD mice. In summary, the BACHD model constitutes a novel and robust in vivo paradigm for the investigation of HD pathogenesis and treatment.

Key words: Huntington's disease; huntingtin; bacterial artificial chromosome; BAC; transgenic mouse; neurodegeneration; polyglutamine; repeat instability; preclinical model

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Received Jan. 4, 2008; revised May 2, 2008; accepted May 4, 2008.

Correspondence should be addressed to X. William Yang, Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, and Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, 695 Charles E. Young Drive, 3524 Gonda, Los Angeles, CA 90095. Email: xwyang{at}mednet.ucla.edu

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