Nature：细胞凋亡新进展

　　

生物通报道，美国加州Genentech公司研发部和Salk研究院分子神经生物学实验室的研究人员在大脑神经连接发育研究项目上取得最新的进展。相关成果公布最新的Nature在线版上，文章揭示了神经连接发育的机制，其中Caspase在其中发挥重要作用。

 

在大脑的神经连接发育过程中，自然地会发生轴突分支与神经元凋亡的事件，这些事件有助神经连接发育，然而，为何轴突分支，神经元死亡，这些机制一直困扰着研究者们。

 

在本文章中，Marc Tessier Lavigne带领的研究小组正准备揭开这一谜题。研究发现β-amyloid precursor protein（β淀粉样前蛋白，生物通注，简称APP），和death receptor 6（死亡受体6，生物通注，简称DR6）具有激发Caspase酶促进细胞进入Caspase介导的细胞死亡程序的功能。DR6在神经发育过程中被广泛表达，在活体中，正常的细胞死亡和轴突分支发育需要有DR6参与。与神经元细胞凋亡不同的是，神经元凋亡需要有caspase3参与，而轴突变性退化需要有caspase6参与，在轴突断裂的过程中caspase被激活。DR6可局部地被表面配机体激活，配机体由营养因子缺乏的状况下被释放出来，同时研究者还鉴定出APPl是DR6的配机体。营养因子缺乏会激发β分泌酶（BACE）依赖的APP从表面脱落。

 

功能研究发现DR6上链接APP的氨基端断裂会导致DR6变性。研究突变的小鼠发现遗传机制可证实这一现象的发生。

研究结果表明，APP和DR6是神经元自我摧毁过程中的重要效应因子，并且细胞外的APP可经过DR6和caspase6被激活，最终导致阿尔茨海默病的发生。（生物通 小茜）

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生物通推荐原文检索：APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

【Abstract】

Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that -amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic-factor deprivation in vitro. Unlike neuronal cell body apoptosis, which requires caspase 3, we show that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation, and we identify APP as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a -secretase (BACE)-dependent manner. Loss- and gain-of-function studies support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer's disease.