Generalized brain and skin proteasome inhibition in Huntington's disease
Generalized brain and skin proteasome inhibition in Huntington's disease
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DOI：
10.1002/ana.20207
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发表时间：
2004-09-01
影响因子：
11.2
通讯作者：
Isacson, O
中科院分区：
文献类型：
--
作者：
Seo, H;Sonntag, KC;Isacson, O
突变的细胞内亨廷顿蛋白在亨廷顿病（HD）患者的组织中广泛表达。亨廷顿蛋白突变体的神经元内核蛋白聚集体存在于HD脑中，表明泛素蛋白酶体系统（UPS）功能障碍。由于许多细胞和组织可以科普异常的基因效应，而其他细胞和组织功能障碍和死亡，我们确定了基因诱导的效应，并考虑了基因引起多种细胞内问题的假设，但严重的病理仅在选定的大脑区域中可见。在这项研究中，我们发现在早期（0-1，没有或很少神经元损失）和晚期（3-4，具有更严重的神经元损失）HD患者的小脑、皮质、黑质和尾壳核脑区域中UPS功能受到抑制。HD晚期泛素水平升高是尾壳核特有的。HD患者的皮肤成纤维细胞也具有与脑相似的UPS抑制，尽管蛋白酶体β亚基表达增加。基因传递和蛋白酶体激活剂PA 28的表达增加了正常但非HD成纤维细胞的UPS功能。这些普遍的UPS问题与严重的神经元病变，只有当再加上脑源性神经营养因子水平的降低，线粒体复合物II/III的活性，特别是在HD患者的尾壳核的泛素水平的增加。
Mutated intracellular huntingtin is widely expressed in tissues of Huntington's disease (HD) patients. Intraneuronal nuclear protein aggregates of mutant huntingtin are present in HD brains, suggesting a dysfunction of the ubiquitin proteasome system (UPS). Because many cells and tissues can cope with the abnormal gene effects while others dysfunction and die, we determined gene-induced effects and considered the hypothesis that the gene causes multiple intracellular problems, but severe pathology is seen only in selected brain regions. In this study, we found inhibition of UPS function in both early (0-1, with no or little neuronal loss) and late (3-4, with more severe neuronal loss) stage HD patients' cerebellum, cortex, substantia nigra and caudate-putamen brain regions. Late HD stage increases in ubiquitin levels were unique to caudate-putamen. HD patients' skin fibroblasts also had UPS inhibition similar to brain despite increases in proteasome beta-subunit expression. Gene delivery and expression of proteasome activator PA28 increased UPS function in normal but not HD fibroblasts. These generalized UPS problems are associated with severe neuronal pathology only when coupled with decreases in brain-derived neurotrophic factor levels, mitochondrial complex II/III activity, and increases of ubiquitin levels particularly as seen in the caudate-putamen of HD patients.