Background The R6/2 mouse model of Huntington’s disease (HD) is one of the most widely used models in HD research and contains human exon1 of HTT with a CAG/polyglutamine (polyQ) repeat expansion. When created the R6/2 line had a repeat expansion of approximately 150Q and because of gametic CAG repeat instability, R6/2 colonies throughout the world now have a wide range of repeat sizes.
Methods We have assessed the behavioural and molecular phenotypes of an R6/2 line with the comparatively stable polyQ-repeat expansion of 90Q. These mice show a slower disease progression with an end point at around 24 weeks of age as opposed to 15 weeks for R6/2 mice with 200Q.
Results Male and female R6/2 Q90 mice displayed decreased body weight, a deficit in rotarod performance and decreased grip strength as well as transcriptional dysregulation in the brain and mutant huntingtin (mHTT) aggregation in brain and muscle.We performed a comparative analysis of dysregulated transcripts and aggregate accumulation for R6/2 Q90 mice and R6/2 Q200 mice at 2, 4 and 8 weeks of age. We found that R6/2 Q90 mice exhibit transcriptional dysregulation and increased aggregation of mHTT in the brain from 4 weeks, whereas the same changes were not apparent in the R6/2 Q200 mice until 8 weeks of age. In muscle mHTT aggregation occurred earlier in R6/2 Q200 mice than in those with 90Q.
Conlusions We are in the process of investigating the comparative nuclear and cytoplasmic location of mHTT aggregates between these two lines. The R6/2 Q90 mice might provide a useful R6/2 strain for pharmacodynamic analyses as these fundamental molecular phenotypes occur very rapidly whilst the stability of the repeat expansion makes the colony easier to maintain than that with 200Q. This work was funded by the CHDI Foundation.
- Huntington’s disease
- mouse model
- transcriptional dysregulation
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