Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity.
Huntingtin forms toxic NH2-terminal fragment complexes that are promoted by the age-dependent decrease in proteasome activity.
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DOI：
10.1083/jcb.200306038
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发表时间：
2003-10-13
期刊：
影响因子：
--
通讯作者：
Li XJ
中科院分区：
文献类型：
--
作者：
Zhou H;Cao F;Wang Z;Yu ZX;Nguyen HP;Evans J;Li SH;Li XJ
虽然NH2末端突变的Huntingtin(HTT)片段会导致亨廷顿病(HD)的神经系统疾病，但目前尚不清楚有毒的HTT片段是如何产生的，并在疾病过程中起到了作用。在这里，我们报告了在HTT转基因细胞和HD敲击小鼠脑中产生了比前508个氨基酸更小的复杂的NH2末端突变的HTT片段。这些碎片构成神经元核包涵体，出现在神经系统症状之前。这些HTT片段的聚集和聚集与蛋白酶体活性的年龄相关性降低有关，并通过抑制蛋白酶体活性而促进。这些结果表明，蛋白酶体活性降低是HTT迟发性毒性的原因之一，恢复移除NH2末端片段的能力将提供一种比抑制它们的产生更有效的治疗HD的方法。
Although NH2-terminal mutant huntingtin (htt) fragments cause neurological disorders in Huntington's disease (HD), it is unclear how toxic htt fragments are generated and contribute to the disease process. Here, we report that complex NH2-terminal mutant htt fragments smaller than the first 508 amino acids were generated in htt-transfected cells and HD knockin mouse brains. These fragments constituted neuronal nuclear inclusions and appeared before neurological symptoms. The accumulation and aggregation of these htt fragments were associated with an age-dependent decrease in proteasome activity and were promoted by inhibition of proteasome activity. These results suggest that decreased proteasome activity contributes to late onset htt toxicity and that restoring the ability to remove NH2-terminal fragments will provide a more effective therapy for HD than inhibiting their production.
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DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
DOI：
10.1083/jcb.141.5.1097
发表时间：
1998-06-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hackam AS;Singaraja R;Wellington CL;Metzler M;McCutcheon K;Zhang T;Kalchman M;Hayden MR
通讯作者：
Hayden MR
影响因子：
15.9
作者：
DARDEVET, D;SORNET, C;GRIZARD, J
通讯作者：
GRIZARD, J
DOI：
10.1016/s0006-291x(02)00498-9
发表时间：
2002-06-07
影响因子：
3.1
作者：
Hazeki, N;Tsukamoto, T;Kanazawa, I
通讯作者：
Kanazawa, I
影响因子：
5.3
作者：
Martín-Aparicio, E;Yamamoto, A;Lucas, JJ
通讯作者：
Lucas, JJ