RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases
RB1CC1 insufficiency causes neuronal atrophy through mTOR signaling alteration and involved in the pathology of Alzheimer's diseases
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DOI：
10.1016/j.brainres.2007.06.075
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发表时间：
2007-09-07
期刊：
影响因子：
2.9
通讯作者：
Hulette, Christine M.
中科院分区：
文献类型：
--
作者：
Chano, Tokuhiro;Okabe, Hidetoshi;Hulette, Christine M.
RB1诱导的线圈1 （RB1CC1）已被证明是一种新的肿瘤抑制因子，可调节RB1的表达。据报道，RB1CC1的神经元丰度通过维持RB1和mTOR来促进非增殖增大的细胞表型。为了阐明RB1CC1功能不全是否与神经元萎缩和阿尔茨海默病病理有关，我们研究了RB1CC1的修饰是否可能通过干扰神经-2a神经母细胞瘤细胞的mTOR信号传导而导致萎缩或死亡。我们还评估了一系列阿尔茨海默病脑组织中RB1CC1与mTOR信号传导之间的相关性。虽然RB1CC1的引入促进了神经突的生长，但rnai介导的RB1CC1的下调或雷帕霉素的治疗导致分化的神经突萎缩和凋亡，这是由于mTOR信号的减少。TSC1和RB1CC1具有相同的功能，并维持mTOR信号，在69%的阿尔茨海默病（9/13例）和100%的正常大脑（6/6例）中表达磷酸化s6 （Ser240/244）。然而，RB1CC1表达不足，低于TSC1，导致31%（4/13例）的阿尔茨海默病组织中phospho-S6消失。这些发现提示RB1CC1不足可能通过不平衡的TSC1丰度导致mTOR信号抑制，并可能诱导神经元萎缩。这些观察结果可能对阿尔茨海默病的发病机制有启示。(C) 2007 Elsevier B.V.版权所有
RB1-inducible Coiled-Coil 1 (RB1CC1) has been shown to be a novel tumor suppressor regulating RB1 expression. Neuronal abundance of RB1CC1 is reported to contribute to the non-proliferating enlarged cell phenotype through the maintenance of RB1 and mTOR. To clarify whether RB1CC1 insufficiency is involved in neuronal atrophy and Alzheimer's pathology, we investigated modifications of RB1CC1 as a possible cause of atrophy or death through the disturbance of mTOR signaling in Neuro-2a neuroblastoma cells. We also evaluated the correlation between RB1CC1 and mTOR signaling in a series of Alzheimer's brain tissues. Though RB1CC1 introduction enhanced neurite growth, RNAi-mediated knockdown of RB1CC1 or rapamycin treatment caused neurite atrophy and apoptosis due to mTOR signaling reduction in the differentiated Neuro-2a cells. Both TSC1 and RB1CC1 were equally functional and maintained mTOR signaling, indicated by phospho-S6 (Ser240/244) expression in 69% of Alzheimer's (9/13 cases) and 100% of normal brains (6/6 cases). However, scanty RB1CC1 expression, less than TSC1, caused phospho-S6 disappearance in 31% of Alzheimer's tissues (4/13 cases). These findings suggest that RB1CC1 insufficiency may result in mTOR signaling repression through unbalanced TSC1 abundance and may induce neuronal atrophy. These observations may have implications for the pathogenesis of Alzheimer's disease. (C) 2007 Elsevier B.V. All rights reserved.