Transgenic Mouse Model Expressing the Caspase 6 Fragment of Mutant Huntingtin

摘要: Huntington9s disease (HD) is caused by a polyglutamine expansion in the Huntingtin (Htt) protein. Proteolytic cleavage of Htt into toxic N-terminal fragments believed to be key aspect pathogenesis. The best characterized putative event at amino acid 586, hypothesized mediated caspase 6. A corollary 6 hypothesis that fragment should fragment. To test this hypothesis, and further characterize role fragment, we have generated transgenic mice expressing 586 aa with repeat length 82 (N586–82Q), under control prion promoter. N586–82Q show clear progressive rotarod deficit 4 months age, are hyperactive starting 5 months, later changing hypoactivity before early mortality. MRI studies reveal widespread brain atrophy, histologic demonstrate an abundance aggregates, mostly cytoplasmic, which predominantly composed polypeptide. Smaller soluble appear accumulate over time, peaking found nuclear fraction. This model appears phenotype more severe than current full-length models, but less HD mouse models shorter fragments. These suggest may transient intermediate, size factor contributing rate progression, short most relevant