Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase: clues to a possible strategy for treating ALS
Heat-shock protein 105 interacts with and suppresses aggregation of mutant Cu/Zn superoxide dismutase: clues to a possible strategy for treating ALS
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DOI：
10.1111/j.1471-4159.2007.04534.x
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Shimohama, Shun
中科院分区：
文献类型：
--
作者：
Yamashita, Hirofumi;Kawamata, Jun;Shimohama, Shun
铜锌超氧化物歧化酶 (SOD1) 基因的显性突变是遗传性肌萎缩侧索硬化症的最常见原因。突变的 SOD1 通过一种不明的获得性毒性引起运动神经元的进行性退化。利用亲和纯化和质谱分析，我们发现了热休克蛋白 105 (Hsp105) 和突变型 SOD1 之间的新型相互作用。我们在突变型 SOD 1 (G93A) 转基因小鼠的脊髓提取物和培养的神经母细胞瘤细胞中检测到这种相互作用。随着疾病的进展，在小鼠运动神经元中发现的 Hsp105 的表达在 SOD 1 G93A 小鼠的脊髓中表达降低，而另外两种热休克蛋白 Hsp70 和 Hsp27 的表达水平则升高。此外，Hsp105 抑制培养细胞中含有突变型 SOD1 的聚集体的形成。这些结果表明，提高 Hsp105 水平的技术可能是减轻突变型 SOD1 毒性的有前途的工具。
A dominant mutation in the gene for copper-zinc superoxide dismutase (SOD1) is the most frequent cause of the inherited form of amyotrophic lateral sclerosis. Mutant SOD1 provokes progressive degeneration of motor neurons by an unidentified acquired toxicity. Exploiting both affinity purification and mass spectrometry, we identified a novel interaction between heat-shock protein 105 (Hsp105) and mutant SOD1. We detected this interaction both in spinal cord extracts of mutant SOD 1 (G93A) transgenic mice and in cultured neuroblastoma cells. Expression of Hsp105, which is found in mouse motor neu- rons, was depressed in the spinal cords of SOD 1 G93A mice as disease progressed, while levels of expression of two other heat-shock proteins, Hsp70 and Hsp27, were elevated. Moreover, Hsp105 suppressed the formation of mutant SOD1-containing aggregates in cultured cells. These results suggest that techniques that raise levels of Hsp105 might be promising tools for alleviation of the mutant SOD1 toxicity.