限制PSEN2/γ-分泌酶的位置决定了基质的特异性,并产生了细胞内Aβ池
Ragna Sannerud1, Cary Esselens1, Paulina Ejsmont1
1VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium; Department of Human Genetics, KU Leuven, 3000 Leuven, Belgium.
Cell
|June 14, 2016
概括
这项研究揭示了Presenilin 2 (PSEN2) 局部化如何通过指导玛分泌酶活性影响阿尔茨海默病 (AD) 发病. 家族性AD突变进一步增加了毒性β-粉样蛋白在特定细胞区的积累.
科学领域:
- 分子生物学
- 细胞生物学
- 神经科学
背景情况:
- 玛分泌酶是细胞信号传递至关重要的膜内分裂蛋白酶,并与阿尔茨海默病 (AD) 有关.
- 细胞表达含有同类前素 (PSEN1和PSEN2) 的异质玛分泌酶复合体.
- 了解这种异质性的功能意义是阐明AD病变的关键.
研究的目的:
- 调查素异质在玛分泌酶功能和基质特异性的作用.
- 确定PSEN2局部化如何影响粉样β (Aβ) 的产生和积累.
- 研究家族性AD (FAD) 突变对马分泌酶局部化和Aβ生成的影响.
主要方法:
- 在PSEN2中确定一个独特的图案,负责其本地化.
- 分析与AP-1适配器复合物的酸化依赖相互作用.
- 在表达野生类型和突变PSEN1/PSEN2的细胞中评估Aβ的产生和定位.
主要成果:
- 通过与AP-1复合体的相互作用,PSEN2的独特动机将其导向晚期内分体/溶解体.
- 在较晚的内分体/溶解体中,PSEN2选择性地分裂基质,产生较长的Aβ物种.
- 在PSEN2中与FAD相关的突变和PSEN1突变的子集增强了这些酸性部分中较长的Aβ的积累.
- 马分泌酶局部化决定了基质的特异性,而FAD突变则促进了细胞内容易聚合的Aβ42积累.
结论:
- 玛分泌酶复合物的细胞内定位对于基质特异性至关重要.
- 在PSEN1和PSEN2中引起FAD的突变会导致Aβ42在晚期内分体/溶解体中的累积增加.
- 局部化的细胞内反应涉及玛分泌酶在阿尔茨海默病的发病过程中起着重要作用.
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