Isoprenoids, small GTPases and Alzheimer's disease.
Isoprenoids, small GTPases and Alzheimer's disease.
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DOI：
10.1016/j.bbalip.2010.03.014
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Eckert GP
中科院分区：
文献类型：
--
作者：
Hooff GP;Wood WG;Müller WE;Eckert GP
甲氧戊酸途径是大多数真核细胞的重要代谢途径。胆固醇是这一途径的高度公认的产物，但人们对类异戊二烯的合成和功能越来越感兴趣。异戊二烯是一类复杂的生物活性脂类，包括二苯二酚、泛醌、法尼基焦磷酸(FPP)和香叶基焦磷酸(GGPP)。早期的研究表明，在阿尔茨海默病患者的大脑中，长链类异戊二烯二醇减少，而磷酸二氢呋喃和泛醌升高。直到最近，它们的生物活性前体FPP和GGPP的水平还不清楚。这些短链类异戊二烯在某些蛋白质的翻译后修饰中起关键作用，这些蛋白质在众多信号通路中充当分子开关。主要的蛋白质家族属于小GTP酶超家族，由大约150个成员组成。最近的实验证据表明，小的GTP酶成员参与了AD的发病，并激发了人们对FPP和GGPP在蛋白质预烯基化和细胞功能中的作用的兴趣。从这些研究中得出的一个直接预测是，与正常的神经对照组相比，AD大脑中的FPP和GGPP水平将会升高。最近的证据首次显示，人类AD脑组织中FPP和GGPP水平显著升高。AD和对照样本之间的胆固醇水平没有差异。一个明显的结论是，在AD中，FPP和GGPP的动态平衡而不是胆固醇的动态平衡是特定的靶点。由于FPP或GGPP对小分子GTP酶的预酯化对于它们的正常功能是必不可少的，我们认为这两种异戊二烯类物质在AD中上调，导致某些预烯基化蛋白过多，从而导致神经元功能障碍。
The mevalonate-pathway is a crucial metabolic pathway for most eukaryotic cells. Cholesterol is a highly recognized product of this pathway but growing interest is being given to the synthesis and functions of isoprenoids. Isoprenoids are a complex class of biologically active lipids including for example, dolichol, ubiquinone, farnesylpyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Early work had shown that the long-chain isoprenoid dolichol is decreased, but that dolichyl-phosphate and ubiquinone are elevated in brains of Alzheimer´s diseased (AD) patients. Until recently, levels of their biological active precursors FPP and GGPP were unknown. These short-chain isoprenoids are critical in the post translational modification of certain proteins which function as molecular switches in numerous, signaling pathways. The major protein families belong to the superfamily of small GTPases, consisting of roughly 150 members. Recent experimental evidence indicated that members of the small GTPases are involved in AD pathogenesis and stimulated interest in the role of FPP and GGPP in protein prenylation and cell function. A straightforward prediction derived from those studies was that FPP and GGPP levels would be elevated in AD brains as compared with normal neurological controls. For the first time, recent evidence shows significantly elevated levels of FPP and GGPP in human AD brain tissue. Cholesterol levels did not differ between AD and control samples. One obvious conclusion is that homeostasis of FPP and GGPP but not of cholesterol is specifically targeted in AD. Since prenylation of small GTPases by FPP or GGPP is indispensable for their proper function we are proposing that these two isoprenoids are up-regulated in AD resulting in an over abundance of certain prenylated proteins which contributes to neuronal dysfunction.
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影响因子：
2.9
作者：
CHELSKY, D;RUSKIN, B;KOSHLAND, DE
通讯作者：
KOSHLAND, DE
影响因子：
6.6
作者：
Bruce-Keller, Annadora J.;Gupta, Sunita;Markesbery, William R.
通讯作者：
Markesbery, William R.
影响因子：
2.9
作者：
CARROLL, KK;GUTHRIE, N;RAVI, K
通讯作者：
RAVI, K
DOI：
10.1073/pnas.0506001102
发表时间：
2005-09-06
影响因子：
11.1
作者：
Capell, BC;Erdos, MR;Collins, FS
通讯作者：
Collins, FS
影响因子：
4.8
作者：
Dai, Q;Choy, E;Philips, MR
通讯作者：
Philips, MR