Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival
Polyglutamine expansion, protein aggregation, proteasome activity, and neural survival
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DOI：
10.1074/jbc.m107706200
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发表时间：
2002-04-19
影响因子：
4.8
通讯作者：
Keller, JN
中科院分区：
文献类型：
--
作者：
Ding, QX;Lewis, JJ;Keller, JN
亨廷顿氏病（HD）是八种已确定的三重重复神经退行性疾病之一，它们共同由聚谷氨酰胺重复序列的遗传扩增引起。虽然在这些疾病中，聚谷氨酰胺扩张导致神经退行性变的机制正在被深入研究，但聚谷氨酰胺毒性的潜在原因尚未完全阐明。许多研究都集中在蛋白质聚集和蛋白酶体蛋白水解途径在多谷氨酰胺介导的神经变性中的潜在作用。然而，目前尚不清楚聚谷氨酰胺介导的蛋白聚集是否足以诱导细胞死亡，也不清楚蛋白酶体抑制是先于、同时发生还是由于聚谷氨酰胺相关蛋白聚集的形成而发生。为了解决这些聚谷氨酰胺毒性的重要组成部分，在本研究中，我们利用稳定转染聚谷氨酰胺-绿色荧光蛋白构建物的神经SH-SY5Y细胞来检测聚谷氨酰胺扩增对蛋白质聚集、蛋白酶体活性和神经细胞存活的影响。本研究的数据表明，在基础条件下，聚谷氨酰胺扩增不会显著损害蛋白酶体的活性或提高蛋白质聚集的形成，但会显著损害蛋白酶体对应激的反应能力，并增加应激后应激诱导的蛋白质聚集，这些都是在没有神经细胞死亡的情况下发生的。
Huntington's disease (HD) is one of eight established triplet repeat neurodegenerative disorders, which are collectively caused by the genetic expansion of polyglutamine repeats. While the mechanism(s) by which polyglutamine expansion causes neurodegeneration in each of these disorders is being intensely investigated, the underlying cause of polyglutamine toxicity has not been fully elucidated. A number of studies have focused on the potential role of protein aggregation and disruption of the proteasome proteolytic pathway in polyglutamine-mediated neurodegeneration. However, at present it is not clear whether polyglutamine-mediated protein aggregation is sufficient to induce cell death, nor has it been clearly determined whether proteasome inhibition precedes, coincides, or occurs as the result of the formation of polyglutamine-associated protein aggregation. To address these important components of polyglutamine toxicity, in the present study we utilized neural SH-SY5Y cells stably transfected with polyglutamine-green fluorescent protein constructs to examine the effects of polyglutamine expansion on protein aggregation, proteasome activity, and neural cell survival. Data from the present study demonstrate that polyglutamine expansion does not dramatically impair proteasome activity or elevate protein aggregate formation under basal conditions, but does significantly impair the ability of the proteasome to respond to stress, and increases stress-induced protein aggregation following stress, all in the absence of neural cell death.