Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy
Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy
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DOI：
10.1074/jbc.m109633200
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发表时间：
2002-04-05
影响因子：
4.8
通讯作者：
Rubinsztein, DC
中科院分区：
文献类型：
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作者：
Bao, YP;Cook, LJ;Rubinsztein, DC
常染色体显性眼咽肌营养不良 (OPMD) 的病理学特征是骨骼肌中的核内包涵体，是由核内多聚 (A) 结合蛋白 2 (PABP2) 中 10 个丙氨酸延伸至 12-17 个丙氨酸引起的。尽管 PABP2 是 OPMD 内含物的主要成分，但引起疾病的致病机制尚不清楚。在这里，我们表明 PABP2 中的聚丙氨酸扩增导致包涵体数量增加并增强 COS-7 细胞的死亡。我们观察到，与较长和较短的聚丙氨酸延伸相关的核靶向绿色荧光蛋白的蛋白质聚集和细胞死亡有类似的增加。我们的 OPMD 细胞模型中的核内聚集物与热休克蛋白 (HSP) 40 (HDJ-1) 和 HSP70 相关。人类 HDJ-1、酵母 hsp104、细菌衍生的 GroEL 微型伴侣和化学伴侣 Me2SO 在我们的 OPMD 模型中减少了聚集和细胞死亡，而不影响 PABP2 的水平，并且具有长聚丙氨酸延伸的绿色荧光蛋白也观察到类似的趋势。因此，不同蛋白质环境中的聚丙氨酸扩增突变会导致蛋白质错误折叠/聚集并杀死细胞。 OPMD 的情况似乎与多聚谷氨酰胺疾病有许多相似之处，这增加了错误折叠的、易于聚集的蛋白质可能扰乱类似途径的可能性，无论突变或蛋白质背景的性质如何。
Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is characterized pathologically by intranuclear inclusions in skeletal muscles and is caused by the expansion of a 10-alanine stretch to 12-17 alanines in the intranuclear poly(A)-binding protein 2 (PABP2). Whereas PABP2 is a major component of the inclusions in OPMD, the pathogenic mechanisms causing disease are unknown. Here we show that polyalanine expansions in PABP2 cause increased numbers of inclusions and enhance death in COS-7 cells. We observed similar increases of protein aggregation and cell death with nuclear-targeted green fluorescent protein linked to longer versus shorter polyalanine stretches. Intranuclear aggregates in our OPMD cell model were associated with heat shock protein (HSP) 40 (HDJ-1) and HSP70. Human HDJ-1, yeast hsp104, a bacterially derived GroEL minichaperone, and the chemical chaperone Me2SO reduced both aggregation and cell death in our OPMD model without affecting the levels of PABP2, and similar trends were seen with green fluorescent protein with long polyalanine stretches. Thus, polyalanine expansion mutations in different protein contexts cause proteins to misfold/aggregate and kill cells. The situation in OPMD appears to have many parallels with polyglutamine diseases, raising the possibility that misfolded, aggregate-prone proteins may perturb similar pathways, irrespective of the nature of the mutation or protein context.