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E. KUDWA, C. MORIN, S. MILLER, J. FITZPATRICK, R. MUSHLIN, B. ALOSIO, D. HE, C. MURPHY, M. RUIZ, J. WATSON-JOHNSON, K. LEHTIMAKI, J. PUOLIVALI, J. YRJANHEIKKI, S. RAMBOZ, S. KWAK, L. PARK, E. SCHAEFFER, D. HOWLAND, L. MENALLED

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and psychiatric alterations. HD is caused by an unstable expansion of CAG repeats in the gene encoding huntingtin protein. Numerous mouse models have been generated which are invaluable tools to examine not only the pathogenesis of the disease but also to evaluate therapeutic approaches. Of these models, the most precise genetic reproduction of the human condition are the knock-in (KI) mouse models since they express the mutation in the proper genetic and protein context on the murine gene. Spontaneous expansion of the CAG repeat stretch in the CAG 140 KI mouse model, which carries a chimeric mouse/human exon 1 containing around 125 CAG repeats and the human polyproline region inserted in the murine huntingtin gene (Menalled et al., 2003, Hickey et al., 2008), has recently led to a new KI line that carries around 190 CAG repeats (CAG 190 KI) in a congenic C57Bl/6J background. It is known that motor abnormalities in CAG 94 KI and CAG 140 KI mouse models are present from an early age, with a delayed onset observed in the CAG 94 KI model as compared to CAG 140 KI; in addition, overt behavioral deficits were observed after 2 years of age in the CAG 140 KI mouse model (Menalled et al., 2003, Hickey et al., 2008). In the present study we evaluate the motor and cognitive behavior and general health of the new CAG 190 KI line at multiple time points to investigate the onset and progression of disease-related deficits. In addition to these behavioral data, volumetric brain analysis was performed and data will be presented. Results will be compared to the CAG 140 KI parental line. This research was supported by the CHDI Foundation.