Trehalose reverses cell malfunction in fibroblasts from normal and Huntington's disease patients caused by proteosome inhibition.
Trehalose reverses cell malfunction in fibroblasts from normal and Huntington's disease patients caused by proteosome inhibition.
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DOI：
10.1371/journal.pone.0090202
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Mena MA
中科院分区：
文献类型：
--
作者：
Fernandez-Estevez MA;Casarejos MJ;López Sendon J;Garcia Caldentey J;Ruiz C;Gomez A;Perucho J;de Yebenes JG;Mena MA
亨廷顿病（HD）是一种神经退行性疾病，其特征在于进行性运动、认知和精神缺陷，与纹状体神经元的主要损失相关，并且由亨廷顿蛋白中的多聚谷氨酰胺扩增引起。突变亨廷顿蛋白及其片段对蛋白质降解具有抗性，并产生泛素蛋白酶体系统（UPS）的阻断作用。在HD模型中，蛋白酶体抑制剂环氧霉素会加剧蛋白质积累，而自噬诱导剂海藻糖会减少蛋白质积累。我们研究了环氧霉素和海藻糖对对照组和HD患者皮肤成纤维细胞的影响。未经处理的HD成纤维细胞增加了泛素化蛋白的水平和更高水平的活性氧（ROS）、亨廷顿蛋白和自噬标记物LAMP 2A。HD中的基线复制率高于对照成纤维细胞，但在12代后恢复。环氧霉素增加HD和对照组中活化的半胱天冬酶-3，HSP 70，亨廷顿蛋白，泛素化蛋白和ROS水平。用海藻糖处理抵消了环氧霉素诱导的ROS、泛素化蛋白、亨廷顿蛋白和活化的半胱天冬酶-3水平的增加，并且还使HD成纤维细胞中的LC 3水平比对照增加更多。这些结果表明，海藻糖可以逆转亨廷顿病患者的蛋白质加工异常。
Huntington's disease (HD) is a neurodegenerative disorder characterized by progressive motor, cognitive and psychiatric deficits, associated with predominant loss of striatal neurons and is caused by polyglutamine expansion in the huntingtin protein. Mutant huntingtin protein and its fragments are resistant to protein degradation and produce a blockade of the ubiquitin proteasome system (UPS). In HD models, the proteasome inhibitor epoxomicin aggravates protein accumulation and the inductor of autophagy, trehalose, diminishes it. We have investigated the effects of epoxomicin and trehalose in skin fibroblasts of control and HD patients. Untreated HD fibroblasts have increased the levels of ubiquitinized proteins and higher levels of reactive oxygen species (ROS), huntingtin and the autophagy marker LAMP2A. Baseline replication rates were higher in HD than in controls fibroblasts but that was reverted after 12 passages. Epoxomicin increases the activated caspase-3, HSP70, huntingtin, ubiquitinated proteins and ROS levels in both HD and controls. Treatment with trehalose counteracts the increase in ROS, ubiquitinated proteins, huntingtin and activated caspase-3 levels induced by epoxomicin, and also increases the LC3 levels more in HD fibroblast than controls. These results suggest that trehalose could revert protein processing abnormalities in patients with Huntington's Disease.
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DOI：
10.1083/jcb.201110093
发表时间：
2012-03-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hipp MS;Patel CN;Bersuker K;Riley BE;Kaiser SE;Shaler TA;Brandeis M;Kopito RR
通讯作者：
Kopito RR
影响因子：
4.2
作者：
de Bernardo, S;Canals, S;Mena, MA
通讯作者：
Mena, MA
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR
影响因子：
4.2
作者：
Jeong, Ji Cheon;Kim, Saeng Jae;Kim, Ki Hyung
通讯作者：
Kim, Ki Hyung
影响因子：
4.8
作者：
Chondrogianni, N;Stratford, FLL;Gonos, ES
通讯作者：
Gonos, ES