Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain.
Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain.
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DOI：
10.1111/jnc.12654
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发表时间：
2014-05
影响因子：
4.7
通讯作者：
Eckert GP
中科院分区：
文献类型：
--
作者：
Afshordel S;Wood WG;Igbavboa U;Muller WE;Eckert GP
突触损伤而不是神经元丢失可能是大脑老化中认知功能障碍的主要原因。某些小的Rho-GTP酶参与突触可塑性，它们的功能障碍与大脑老化和神经退化有关。Rho-GTP酶通过GGTase-I催化的香叶基香叶基焦磷酸(GGPP)的连接进行预烯基化。我们检测了3个月龄和23个月龄C57BL/6小鼠脑膜和胞浆中Rho-和Rab蛋白的丰度以及脑组织中GGTase-I的年龄相关性变化。我们报告了Rho-GTP酶细胞定位的转变，与年轻小鼠相比，老年小鼠脑中这些蛋白的膜相关水平降低，胞浆水平升高。与年龄相关的膜相关Rho蛋白的减少与调节GGPP与Rho-GTP酶结合的GGTase-I水平的降低有关。被GGTase-II预基化的蛋白质在老年脑中没有减少，这表明GGTase-I在老年脑中具有特异性靶向。体外对GGTase-I的抑制模拟了我们在体内观察到的衰老效应。我们首次证实了老年脑中膜相关Rho蛋白的减少与GGTase-I的下调有关。这种下调可能是导致与年龄相关的突触可塑性减弱的机制之一。
Synaptic impairment rather than neuronal loss may be the leading cause of cognitive dysfunction in brain aging. Certain small Rho-GTPases are involved in synaptic plasticity, and their dysfunction is associated with brain aging and neurodegeneration. Rho-GTPases undergo prenylation by attachment of geranylgeranylpyrophosphate (GGPP) catalyzed by GGTase-I. We examined age-related changes in the abundance of Rho- and Rab proteins in membrane and cytosolic fractions as well as of GGTase-I in brain tissue of 3 and 23 mo old C57BL/6 mice. We report a shift in the cellular localization of Rho-GTPases towards reduced levels of membrane-associated and enhanced cytosolic levels of those proteins in aged mouse brain as compared with younger mice. The age-related reduction of membrane-associated Rho-proteins was associated with a reduction in GGTase-I levels that regulates binding of GGPP to Rho-GTPases. Proteins prenylated by GGTase-II were not reduced in aged brain indicating a specific targeting of GGTase-I in the aged brain. Inhibition of GGTase-I in vitro modeled the effects of aging we observed in vivo. We demonstrate for the first time a decrease of membrane-associated Rho proteins in aged brain in association with down-regulation of GGTase-I. This down-regulation could be one of the mechanisms causing age-related weakening of synaptic plasticity.
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DOI：
10.1016/j.jpba.2004.11.006
发表时间：
2005-03-09
影响因子：
3.4
作者：
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影响因子：
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发表时间：
2007-01-09
影响因子：
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DOI：
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发表时间：
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影响因子：
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