Longitudinal comparison of disease progression in three knockin HD mouse models with a similar CAG expansion repeat size: z_Q175, z_Q175DN and Mc_CAG170

1PsychoGenics, Inc., Paramus, NJ, USA;  2CHDI Foundation, Los Angeles, CA, USA;
3CHDI Foundation, Princeton, NJ, USA;

Disease progression was compared in three knockin mouse lines with similar CAG repeat expansion lengths of approximately 190 repeats, were compared at 2, 4, 6 and 10 months of age utilizing PsychoGenics proprietary cubes platform technologies: PhenoCube®, Smart Cube® and Neurocube® as well as standard behavioral testing paradigms including Open Field and Tapered Balance Beam.

Heterozygous mice from two newly described lines z_Q175DN (z_Q175 line with 5’ flanking neoR cassette excised) and the Mc_CAG170 line (generated at MGH) were compared to heterozygous mice from the well characterized z_Q175 line. PhenoCube® analysis revealed a robust discrimination in behavioral features as early as 2 months of age in the z_Q175 line when compared to their wild-type littermates. This early discrimination in behavioral features was also evident in the z_Q175DN line when comparing heterozygous mice and their wild-type littermates, however, the discrimination probability was lower with this line when compared to the well characterized z_Q175 line. While demonstrating early phenotypic differences in the PhenoCube®, both the z_Q175 and z_Q175DN lines failed to show a progression in behavioral feature discrimination with age. In comparison, the Mc_CAG170 line while also showing a robust discrimination in phenotypic differences in the PhenoCube® as early as 2months of age, showed a progression in phenotypic discrimination with age. All three lines demonstrated an expected decrease in activity in heterozygous mice beginning at 4months of age, with the Mc_CAG170 line showing a consistent reduction in activity with age when heterozygous mice were compared to their wild-type littermates. This difference in activity between heterozygous mice and their wild-type littermates was not as robust in the z_Q175 and z_Q175DN lines at later ages due to a concurrent decrease in activity in their wild-type littermates with age. Tapered balance beam testing revealed deficits in coordination in the z_Q175 and the Mc_CAG170 lines beginning at 10months of age, that were not detected in the z_Q175DN line.


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