BACHD transgenic Rat Model

Huntington disease (HD) is an autosomal-dominantly inherited, fatal, neurodegenerative disorder. Patients present with motor dysfunction, psychiatric disturbances, cognitive impairments and metabolic abnormalities. These behavioral changes are directly associated with the dysfunction and degeneration of certain brain areas, most prominently striatum and cortex. The sole cause of developing HD is the expansion of an unstable repeat of CAG base triplets in the coding region of the Huntingtin gene, HTT. CAG repeat lengths up to 34 are considered to lie in the normal range, while more than 35 CAG repeats lead most likely to the development of HD. The age of disease onset correlates inversely with CAG repeat length and lies on average at the age of 40–50 years.

In HD patients, the mHTT allele is translated into a mutated protein (mutant huntingtin, mHTT), which carries an abnormally long glutamine (polyQ) stretch after amino acid 17 close to the N-terminus. Similar to the normal huntingtin protein (HTT), mHTT is abundant throughout the body, even though degenerative processes are restricted to selective neuronal tissues. In contrast to HTT, mHTT shows an abnormally high concentration in cell nuclei. In addition, mHTT-expressing cells develop mHTT-containing protein aggregates in both nucleus and neurites. The presence of the elongated polyQ stretch leads to a disruption of normal HTT function as well as a toxic gain of function. The pathogenic events in HD are related to intracellular transport, gene as well as protein expression, protein degradation pathways, cellular energy metabolism, ion homeostasis, cell signaling and apoptosis.

BACHD rats overexpress full-length human mHTT with 97 alternating CAA/CAG repeats on a bacterial artificial chromosome (BAC).

Figure BACHD rats - Huntington's diseaseFigure 1: Rotarod and Morris water maze-reversal learning. A: Rotarod test was performed from month 1 to 5. Latency to fall off the rod in seconds. B: 7-month old BACHD rats present with a significantly longer latency to find the platform in the reversal trials on day 9of testing, animals present no learning deficits during the first 8 days of training (data not shown). Two-way ANOVA followed by Bonferroni posthoc test. Mean ± SEM. N = 15 per group. **p<0.01 ***p<0.001.

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