共 70 条
Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice
被引:70
作者:

Schilling, G
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Savonenko, AV
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Klevytska, A
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Morton, JL
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Tucker, SM
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Poirier, M
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Gale, A
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Chan, N
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Gonzales, V
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Slunt, HH
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Coonfield, ML
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Jenkins, NA
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Copeland, NG
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Ross, CA
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

Borchelt, DR
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机构: Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
机构:
[1] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA
[4] NCI, Mouse Canc Genet Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA
关键词:
D O I:
10.1093/hmg/ddh175
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Huntington's disease (HD) results from the expansion of a glutamine repeat near the N-terminus of huntingtin (htt). At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions. This pathology has been reproduced in transgenic mice expressing the first 171 amino acids of htt with 82 glutamines along with losses of motoric function, hypoactivity and abbreviated life-span. The relative contributions of nuclear versus cytoplasmic mutant htt to the pathogenesis of disease have not been clarified. To examine whether pathogenic processes in the nucleus disproportionately contribute to disease features in vivo, we fused a nuclear localization signal (NLS) derived from atrophin-1 to the N-terminus of an N171-82Q construct. Two lines of mice (lines 8A and 61) that were identified expressed NLS-N171-82Q at comparable levels and developed phenotypes identical to our previously described HD-N171-82Q mice. Western blot and immunohistochemical analyses revealed that NLS-N171-82Q fragments accumulate in nuclear, but not cytoplasmic, compartments. These data suggest that disruption of nuclear processes may account for many of the disease phenotypes displayed in the mouse models generated by expressing mutant N-terminal fragments of htt.
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页码:1599 / 1610
页数:12
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