Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients.
Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients.
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DOI：
10.1016/j.nbd.2009.05.005
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发表时间：
2009-08
影响因子：
6.1
通讯作者：
Wood WG
中科院分区：
文献类型：
--
作者：
Eckert GP;Hooff GP;Strandjord DM;Igbavboa U;Volmer DA;Müller WE;Wood WG
法呢基-（FPP）和香叶基香叶基焦磷酸（GGPP）对小GTP酶的翻译后修饰由于其对癌症、心血管和神经退行性疾病的潜在贡献而引起了广泛的关注。异戊烯化的蛋白质已被确定在许多细胞功能和FPP和GGPP的水平升高先前已提出发生在阿尔茨海默病（AD），但从来没有被量化。在本研究中，我们确定与对照样品相比，甲羟戊酸衍生的化合物FPP和GGPP在男性AD患者的脑灰质和白色物质中是否增加。本研究首次证明，FPP和GGPP水平在人AD灰质和白色物质中显著升高，但胆固醇没有升高，表明类异戊二烯调节的潜在疾病特异性靶向独立于HMG-CoA还原酶。进一步表明AD中FPP和GGPP稳态的选择性破坏，我们表明体内HMG-CoA还原酶的抑制显著降低了小鼠中FPP、GGPP和胆固醇丰度，对类异戊二烯的影响最大。一个初步的结论是，如果FPP和GGPP的调节确实改变了AD脑中的这种变化可能会刺激蛋白质异戊二烯化，并有助于AD的神经病理生理。
Post-translational modification of small GTPases by farnesyl- (FPP) and geranylgeranylpyrophosphate (GGPP) has generated much attention due to their potential contribution to cancer, cardiovascular and neurodegenerative diseases. Prenylated proteins have been identified in numerous cell functions and elevated levels of FPP and GGPP have been previously proposed to occur in Alzheimer disease (AD) but have never been quantified. In the present study, we determined if the mevalonate derived compounds FPP and GGPP are increased in brain grey and white matter of male AD patients as compared with control samples. This study demonstrates for the first time that FPP and GGPP levels are significantly elevated in human AD grey and white matter but not cholesterol, indicating a potentially disease-specific targeting of isoprenoid regulation independent of HMG-CoA-reductase. Further suggesting a selective disruption of FPP and GGPP homeostasis in AD, we show that inhibition of HMG-CoA reductase in vivo significantly reduced FPP, GGPP and cholesterol abundance in mice with the largest effect on the isoprenoids. A tentative conclusion is that if indeed regulation of FPP and GGPP is altered in AD brain such changes may stimulate protein prenylation and contribute to AD neuropathophysiology.
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影响因子：
2.1
作者：
Sparks, D. Larry;Kryscio, Richard J.;Liebsack, Carolyn
通讯作者：
Liebsack, Carolyn
影响因子：
82.9
作者：
Kukar, T;Murphy, MP;Golde, TE
通讯作者：
Golde, TE
影响因子：
2.9
作者：
Tong, HX;Holstein, SA;Hohl, RJ
通讯作者：
Hohl, RJ
影响因子：
4.3
作者：
Hooff, Gero P.;Volmer, Dietrich A.;Wood, W. Gibson;Mueller, Walter E.;Eckert, Gunter P.
通讯作者：
Eckert, Gunter P.
影响因子：
3.5
作者：
Dumanchin, C;Czech, C;Frebourg, T
通讯作者：
Frebourg, T