Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration
Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration
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DOI：
10.1038/ncomms2417
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Kondo, Naohide;Katsuno, Masahisa;Sobue, Gen
成人发病的神经退行性疾病的一个重要特征是异常蛋白质在特定脑区的积累，尽管这种病理选择性的机制尚不清楚。热休克因子-1是热休克蛋白的转录调节因子，热休克蛋白是通过重折叠和溶解致病蛋白来消除神经变性的分子伴侣。在这里，我们表明，热休克因子-1的表达水平与脊髓和延髓肌萎缩症，多聚谷氨酰胺诱导的神经退行性疾病的致病性雄激素受体的积累。在杂合子热休克因子-1基因敲除的脊髓和延髓肌萎缩小鼠中，异常雄激素受体在大脑视觉皮层、肝脏和垂体中积累，而在其基因未修饰的对应物中不受影响。热休克因子-1的耗竭也扩大了其他神经元区域中致病性雄激素受体积累的分布。此外，慢病毒介导的热休克因子-1传递到脊髓和延髓肌萎缩小鼠的脑中局部抑制致病性雄激素受体积累和神经元萎缩。这些结果表明，热休克因子-1影响脊髓和延髓肌萎缩症的病理损伤的选择性。
A crucial feature of adult-onset neurodegenerative diseases is accumulation of abnormal protein in specific brain regions, although the mechanism underlying this pathological selectivity remains unclear. Heat shock factor-1 is a transcriptional regulator of heat shock proteins, molecular chaperones that abrogate neurodegeneration by refolding and solubilizing pathogenic proteins. Here we show that heat shock factor-1 expression levels are associated with the accumulation of pathogenic androgen receptor in spinal and bulbar muscular atrophy, a polyglutamine-induced neurodegenerative disease. In heterozygous heat shock factor-1-knockout spinal and bulbar muscular atrophy mice, abnormal androgen receptor accumulates in the cerebral visual cortex, liver and pituitary, which are not affected in their genetically unmodified counterparts. The depletion of heat shock factor-1 also expands the distribution of pathogenic androgen receptor accumulation in other neuronal regions. Furthermore, lentiviral-mediated delivery of heat shock factor-1 into the brain of spinal and bulbar muscular atrophy mice topically suppresses the pathogenic androgen receptor accumulation and neuronal atrophy. These results suggest that heat shock factor-1 influences the pathological lesion selectivity in spinal and bulbar muscular atrophy.