SCAMP5 Links Endoplasmic Reticulum Stress to the Accumulation of Expanded Polyglutamine Protein Aggregates via Endocytosis Inhibition
SCAMP5 Links Endoplasmic Reticulum Stress to the Accumulation of Expanded Polyglutamine Protein Aggregates via Endocytosis Inhibition
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DOI：
10.1074/jbc.m807620200
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发表时间：
2009-04-24
影响因子：
4.8
通讯作者：
Jung, Yong-Keun
中科院分区：
文献类型：
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作者：
Noh, Jee-Yeon;Lee, Huikyong;Jung, Yong-Keun
扩展的多聚谷氨酰胺蛋白的积累被认为是亨廷顿病的主要致病生物标志物。我们使用基于细胞的聚集试验分离出SCAMP 5作为扩展多聚谷氨酰胺轨道蛋白细胞积累的新型调节剂。SCAMP 5的异位表达增强了突变亨廷顿蛋白（mtHTT）的泛素阳性和洗涤剂抗性聚集体的形成。SCAMP 5的表达在亨廷顿病患者的纹状体中显著增加，并且在培养的纹状体神经元中由内质网（ER）应激或由mtHTT诱导。SCAMP 5的增加削弱了内吞作用，这反过来又增强了mtHTT聚集。相反，SCAMP 5的下调可增强内质网应激诱导的mtHTT聚集和内吞抑制。此外，立体定向注射到纹状体和腹腔注射衣霉素显着增加mtHTT聚集在纹状体的R6/2小鼠和N171- 82 Q小鼠的皮质，分别。总之，这些结果表明，暴露于ER应激增加了纹状体中的SCAMP 5，其通过内吞作用途径正向调节mtHTT聚集。
Accumulation of expanded polyglutamine proteins is considered to be a major pathogenic biomarker of Huntington disease. We isolated SCAMP5 as a novel regulator of cellular accumulation of expanded polyglutamine track protein using cell-based aggregation assays. Ectopic expression of SCAMP5 augments the formation of ubiquitin-positive and detergent-resistant aggregates of mutant huntingtin (mtHTT). Expression of SCAMP5 is markedly increased in the striatum of Huntington disease patients and is induced in cultured striatal neurons by endoplasmic reticulum (ER) stress or by mtHTT. The increase of SCAMP5 impairs endocytosis, which in turn enhances mtHTT aggregation. On the contrary, down-regulation of SCAMP5 alleviates ER stress-induced mtHTT aggregation and endocytosis inhibition. Moreover, stereotactic injection into the striatum and intraperitoneal injection of tunicamycin significantly increase mtHTT aggregation in the striatum of R6/2 mice and in the cortex of N171-82Q mice, respectively. Taken together, these results suggest that exposure to ER stress increases SCAMP5 in the striatum, which positively regulates mtHTT aggregation via the endocytosis pathway.