A Novel BACHD Transgenic Rat Exhibits Characteristic Neuropathological Features of Huntington Disease

Abstract

Huntington disease (HD) is an inherited progressive neurodegenerative disorder, characterized by motor, cognitive, and psychiatric deficits as well as neurodegeneration and brain atrophy beginning in the striatum and the cortex and extending to other subcortical brain regions. The genetic cause is an expansion of the CAG repeat stretch in the HTT gene encoding huntingtin protein (htt). Here, we generated an HD transgenic rat model using a human bacterial artificial chromosome (BAC), which contains the full-length HTT genomic sequence with 97 CAG/CAA repeats and all regulatory elements. BACHD transgenic rats display a robust, early onset and progressive HD-like phenotype including motor deficits and anxiety-related symptoms. In contrast to BAC and yeast artificial chromosome HD mouse models that express full-length mutant huntingtin, BACHD rats do not exhibit an increased body weight. Neuropathologically, the distribution of neuropil aggregates and nuclear accumulation of N-terminal mutant huntingtin in BACHD rats is similar to the observations in human HD brains. Aggregates occur more frequently in the cortex than in the striatum and neuropil aggregates appear earlier than mutant htt accumulation in the nucleus. Furthermore, we found an imbalance in the striatal striosome and matrix compartments in early stages of the disease. In addition, reduced dopamine receptor binding was detectable by in vivo imaging. Our data demonstrate that this transgenic BACHD rat line may be a valuable model for further understanding the disease mechanisms and for preclinical pharmacological studies.

Transgenic Rat Models of Huntington’s Disease

“…Very recently, a second transgenic rat model has been described (Yu-Taeger et al 2012). This BACHD transgenic rat expresses the full-length human mutant HTT under the control of the human HTT promoter and all its regulatory elements (Yu-Taeger et al 2012).…”

“…This BACHD transgenic rat expresses the full-length human mutant HTT under the control of the human HTT promoter and all its regulatory elements (Yu-Taeger et al 2012).…”

“…Determination of BAC transgene integrity and genotype was done by PCR analysis of genomic DNA extracted from ear biopsy tissue (Yu-Taeger et al 2012). The BACHD construct was designed by using a BAC containing the full 170 kb of the HTT genomic locus with approximately 20 kb upstream and 50 kb downstream flanking sequences (Yu-Taeger et al 2012). Wild-type (WT) HTT exon 1 was replaced by mutant HTT exon 1 containing 97 mixed CAA/CAG repeats flanked by two LoxP sites.…”

“…Therefore, the BAC construct permitted a conditional and inducible elimination of the mutant HTT exon 1 by Causes recombination (Cre) recombinase activity. The number of CAG repeats was analysed and the conclusion was that the polyQ encoding sequence was stable in different brain regions, at different ages and gender over the generations (Yu-Taeger et al 2012). …”

“…The BACHD animals have been evaluated using the rotarod test and the footprint analysis method (Yu-Taeger et al 2012). The rotarod performance was significantly worse in the transgenic animals already at 1 month of age, which further deteriorated with disease progression.…”