E. KUDWA, C. MORIN, J. LACSINA, Z. DING, D. HE, A. CHEN, A. PARACHIKOVA, C. LEAHY, M. RUIZ, C. ALEXA, R. MUSHLIN, M. PATRY, C. MURPHY, L. PARK, D. HOWLAND, S. RAMBOZ, L. MENALLED
The genetic basis of Huntington’s disease (HD) is the presence of expanded CAG repeats in the huntingtin gene. Previous reports using the R6/2 mouse model suggest that polyQ length may not have a direct linear relationship to the degree of pathogenicity in HD. The current study evaluates how CAG repeat number affects both the age of onset and the progression of disease in the R6/2 mouse model of Huntington’s disease (Mangiarini et al., 1996) by concurrently evaluating R6/2 mice with either 110 or 240 CAG repeats in an F1 hybrid background (C57Bl/6 x CBA/CaJ). The animals were assessed with a motor test battery including open field, rearing-climbing, grip strength and rotarod while cognitive effects were evaluated using cued and procedural versions of the 2-choice swim test. In addition, neurological assessment batteries were run. Body weight and survival were also monitored. Behaviorally and phenotypically, the two R6/2 models showed distinct characteristics. While 80% or more of the 110 CAG mice displayed clasping from 8 weeks of age onwards, only 15-30% of the 240 CAG mice displayed clasping at 14-18 weeks of age and a max of 70% clasped at 19 weeks of age. In addition, 110 CAG mice exhibited tremors at rest at early ages, but the 240 CAG mice only showed tremors at later ages and only after manipulation. No seizures were observed in either cohort. Behaviorally, the mice with 110 CAG repeats showed a sharp decline in both rotarod and open field performance from around 4 weeks of age whereas the 240 CAG repeat mice displayed a 2-3 week delay in the onset of behavioral decline with a much slower progression of decline in both tasks as compared to 110 CAG repeat counterparts. Delays in the decline of cognitive performance were also observed in the 240 CAG repeat mice. In the climbing task, 90% of the 110 CAG mice stopped climbing by 6 weeks of age in contrast to the 240 CAG repeat cohort in which only 55% had stopped climbing by 8 weeks of age. Furthermore, the onset of death in the 240 CAG mice was delayed by 3-4 weeks, but once initiated the progression was faster than that observed in the 110 CAG mice and resulted in median survivals that differed by 1.5 weeks. Overall, these findings indicate that both 110 and 240 CAG repeat R6/2 mice may serve as useful models for the study of Huntington’s disease and may reflect different aspects of the disease.