Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin.
Transgenic mouse model expressing the caspase 6 fragment of mutant huntingtin.
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DOI：
10.1523/jneurosci.1305-11.2012
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发表时间：
2012-01-04
期刊：
影响因子：
--
通讯作者：
Ross CA
中科院分区：
文献类型：
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作者：
Waldron-Roby E;Ratovitski T;Wang X;Jiang M;Watkin E;Arbez N;Graham RK;Hayden MR;Hou Z;Mori S;Swing D;Pletnikov M;Duan W;Tessarollo L;Ross CA
Huntington’s disease (HD) is caused by a polyglutamine expansion in the Huntingtin (Htt) protein. Proteolytic cleavage of Htt into toxic N-terminal fragments is believed to be a key aspect of pathogenesis. The best characterized putative cleavage event is at amino acid 586, hypothesized to be mediated by caspase 6. A corollary of the caspase 6 cleavage hypothesis is that the caspase 6 fragment should be a toxic fragment. To test this hypothesis, and further characterize the role of this fragment, we have generated transgenic mice expressing the N-terminal 586 aa of Htt with a polyglutamine repeat length of 82 (N586-82Q), under the control of the prion promoter. N586-82Q mice show a clear progressive rotarod deficit by four months of age, and are hyperactive starting at 5 months, later changing to hypoactivity prior to early mortality. MRI studies reveal widespread brain atrophy, and histologic studies demonstrate an abundance of Htt aggregates, mostly cytoplasmic, which are predominantly composed of the N586-82Q polypeptide. Smaller soluble N-terminal fragments appear to accumulate over time, peaking at four months, and are predominantly found in the nuclear fraction. This model appears to have a phenotype more severe than current full-length Htt models, but less severe than HD mouse models expressing shorter Htt fragments. These studies suggest that the caspase 6 fragment may be a transient intermediate, that fragment size is a factor contributing to the rate of disease progression, and that short soluble nuclear fragments may be most relevant to pathogenesis.
