CAG repeat lengths ≥ 335 attenuate the phenotype in the R6/2 Huntington's disease transgenic mouse

With spontaneous elongation of the CAG repeat in the R6/2 transgene to ≥ 335, resulting in a transgene protein too large for passive entry into nuclei via the nuclear pore, we observed an abrupt increase in lifespan to > 20 weeks, compared to the 12 weeks common in R6/2 mice with 150 repeats. In the ≥ 335 CAG mice, large ubiquitinated aggregates of mutant protein were common in neuronal dendrites and perikaryal cytoplasm, but intranuclear aggregates were small and infrequent. Message and protein for the ≥ 335 CAG transgene were reduced to one-third that in 150 CAG R6/2 mice. Neurological and neurochemical abnormalities were delayed in onset and less severe than in 150 CAG R6/2 mice. These findings suggest that polyQ length and pathogenicity in Huntington's disease may not be linearly related, and pathogenicity may be less severe with extreme repeats. Both diminished mutant protein and reduced nuclear entry may contribute to phenotype attenuation.