Novel BAC Mouse Model of Huntington's Disease with 225 CAG Repeats Exhibits an Early Widespread and Stable Degenerative Phenotype

Article type: Research Article

Authors: Wegrzynowicz, Michal^; | Bichell, Terry Jo^{; ;} | Soares, Barbara D. | Loth, Meredith K. | McGlothan, Jennifer L. | Alikhan, Fatima S. | Hua, Kegang | Coughlin, Jennifer M. | Holt, Hunter K. | Jetter, Christopher S. | Mori, Susumu | Pomper, Martin G. | Osmand, Alexander P. | Guilarte, Tomás R.^; | Bowman, Aaron B.^{; ; ; ;}

Affiliations: Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA | Vanderbilt University Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, TN, USA | Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA | Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, TN, USA | Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA | Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York City, NY, USA | Department of Radiology, John Hopkins Medical Institutions, Baltimore, MD, USA | Department of Psychiatry, Johns Hopkins Medical Institutions, Baltimore, MD, USA | Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA

Note: [] These authors contributed equally to this manuscript.

Note: [] These authors contributed equally to this manuscript.

Note: [] Correspondence to: Aaron Bowman, Department of Neurology, Vanderbilt University Medical Center, 6110C MRBIII, 465 21st Ave South, Nashville, TN 37232-8552, USA. Tel.: +1 615 322 2651; Fax: +1 615 322 0486; E-mail: [email protected]

Abstract: Background: Unusually large CAG repeat expansions (>60) in exon one of Huntingtin (HTT) are invariably associated with a juvenile-onset form of Huntington's disease (HD), characterized by a more extensive and rapidly progressing neuropathology than the more prevalent adult-onset form. However, existing mouse models of HD that express the full-length Htt gene with CAG repeat lengths associated with juvenile HD (ranging between ~75 to ~150 repeats in published models) exhibit selective neurodegenerative phenotypes more consistent with adult-onset HD. Objective: To determine if a very large CAG repeat (>200) in full-length Htt elicits neurodegenerative phenotypes consistent with juvenile HD. Methods: Using a bacterial artificial chromosome (BAC) system, we generated mice expressing full-length mouse Htt with ~225 CAG repeats under control of the mouse Htt promoter. Mice were characterized using behavioral, neuropathological, biochemical and brain imaging methods. Results: BAC-225Q mice exhibit phenotypes consistent with a subset of features seen in juvenile-onset HD: very early motor behavior abnormalities, reduced body weight, widespread and progressive increase in Htt aggregates, gliosis, and neurodegeneration. Early striatal pathology was observed, including reactive gliosis and loss of dopamine receptors, prior to detectable volume loss. HD-related blood markers of impaired energy metabolism and systemic inflammation were also increased. Aside from an age-dependent progression of diffuse nuclear aggregates at 6 months of age to abundant neuropil aggregates at 12 months of age, other pathological and motor phenotypes showed little to no progression. Conclusions: The HD phenotypes present in animals 3 to 12 months of age make the BAC-225Q mice a unique and stable model of full-length mutant Htt associated phenotypes, including body weight loss, behavioral impairment and HD-like neurodegenerative phenotypes characteristic of juvenile-onset HD and/or late-stage adult-onset HD.

Keywords: Huntington's disease, juvenile HD, Huntingtin, transgenic mouse, neurodegeneration, body weight deficiency, Translocator Protein 18 kDa (TSPO), brain atrophy, blood markers, Htt aggregates, inclusion bodies

DOI: 10.3233/JHD-140116

Journal: Journal of Huntington's Disease, vol. 4, no. 1, pp. 17-36, 2015