美國加州Genentech公司研發(fā)部和Salk研究院分子神經(jīng)生物學實驗室的研究人員在大腦神經(jīng)連接發(fā)育研究項目上取得最新的進展,。相關成果公布最新的Nature在線版上,，文章揭示了神經(jīng)連接發(fā)育的機制，其中Caspase在其中發(fā)揮重要作用,。
在大腦的神經(jīng)連接發(fā)育過程中,，自然地會發(fā)生軸突分支與神經(jīng)元凋亡的事件，這些事件有助神經(jīng)連接發(fā)育,，然而,，為何軸突分支，神經(jīng)元死亡,，這些機制一直困擾著研究者們,。
在本文章中，Marc Tessier Lavigne帶領的研究小組正準備揭開這一謎題,。研究發(fā)現(xiàn)β-amyloid precursor protein（β淀粉樣前蛋白,，簡稱APP），和death receptor 6（死亡受體6,，簡稱DR6）具有激發(fā)Caspase酶促進細胞進入Caspase介導的細胞死亡程序的功能,。DR6在神經(jīng)發(fā)育過程中被廣泛表達，在活體中,，正常的細胞死亡和軸突分支發(fā)育需要有DR6參與,。與神經(jīng)元細胞凋亡不同的是，神經(jīng)元凋亡需要有caspase3參與,，而軸突變性退化需要有caspase6參與,，在軸突斷裂的過程中caspase被激活。DR6可局部地被表面配機體激活,，配機體由營養(yǎng)因子缺乏的狀況下被釋放出來,，同時研究者還鑒定出APPl是DR6的配機體。營養(yǎng)因子缺乏會激發(fā)β分泌酶（BACE）依賴的APP從表面脫落,。
功能研究發(fā)現(xiàn)DR6上鏈接APP的氨基端斷裂會導致DR6變性,。研究突變的小鼠發(fā)現(xiàn)遺傳機制可證實這一現(xiàn)象的發(fā)生。
研究結果表明,，APP和DR6是神經(jīng)元自我摧毀過程中的重要效應因子,，并且細胞外的APP可經(jīng)過DR6和caspase6被激活，最終導致阿爾茨海默病的發(fā)生。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 457, 981-989 (19 February 2009) | doi:10.1038/nature07767
APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Anatoly Nikolaev1, Todd McLaughlin2, Dennis D. M. O'Leary2 & Marc Tessier-Lavigne1
1 Division of Research, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA
2 Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
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.
