Histone deacetylase inhibitors reduce polyglutamine toxicity
Histone deacetylase inhibitors reduce polyglutamine toxicity
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DOI：
10.1073/pnas.261400698
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发表时间：
2001-12-18
影响因子：
11.1
通讯作者：
Fischbeck, KH
中科院分区：
文献类型：
--
作者：
McCampbell, A;Taye, AA;Fischbeck, KH
多聚谷氨酰胺疾病包括至少九种神经退行性疾病，每种疾病都是由不同基因中的 CAG 重复扩增引起的。患者体内会发生突变的含聚谷氨酰胺蛋白的积累，细胞培养和动物实验的证据表明细胞核是发病机制的一个部位。为了了解核积累的后果，我们创建了具有核靶向聚谷氨酰胺的细胞培养系统。在我们的系统中，可以通过全长 cAMP 反应元件结合蛋白 (CREB) 结合蛋白 (CBP) 或其氨基末端部分的过表达来减轻细胞死亡。 CBP 是被聚谷氨酰胺包裹体隔离的几种组蛋白乙酰转移酶之一。我们发现表达突变型聚谷氨酰胺的细胞中组蛋白乙酰化减少。这种低乙酰化的逆转可以通过 CBP 或其氨基末端的过度表达或通过脱乙酰酶抑制剂处理来实现，从而减少细胞损失。这些发现表明，多聚谷氨酰胺的核积累可导致神经元中蛋白质乙酰化的改变，并为多聚谷氨酰胺疾病提供了一种新的治疗策略。
Polyglutamine diseases include at least nine neurodegenerative disorders, each caused by a CAG repeat expansion in a different gene. Accumulation of mutant polyglutamine-containing proteins occurs in patients, and evidence from cell culture and animal experiments suggests the nucleus as a site of pathogenesis. To understand the consequences of nuclear accumulation, we created a cell culture system with nuclear-targeted polyglutamine. In our system, cell death can be mitigated by overexpression of full-length cAMP response element binding protein (CREB)-binding protein (CBP) or its aminoterminal portion alone. CBP is one of several histone acetyltransferases sequestered by polyglutamine inclusions. We found histone acetylation to be reduced in cells expressing mutant polyglutamine. Reversal of this hypoacetylation, which can be achieved either by overexpression of CBP or its amino terminus or by treatment with deacetylase inhibitors, reduced cell loss. These findings suggest that nuclear accumulation of polyglutamine can lead to altered protein acetylation in neurons and indicate a novel therapeutic strategy for polyglutamine disease.