Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila.
Control of Alzheimer's amyloid beta toxicity by the high molecular weight immunophilin FKBP52 and copper homeostasis in Drosophila.
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DOI：
10.1371/journal.pone.0008626
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发表时间：
2010-01-13
期刊：
影响因子：
3.7
通讯作者：
Konsolaki M
中科院分区：
文献类型：
--
作者：
Sanokawa-Akakura R;Cao W;Allan K;Patel K;Ganesh A;Heiman G;Burke R;Kemp FW;Bogden JD;Camakaris J;Birge RB;Konsolaki M
FK 506结合蛋白（FKBP），也称为亲免蛋白，是脯氨酰异构酶（PPI酶），参与多种细胞功能，包括激素信号传导和蛋白质折叠。最近的研究表明，含有PPIase活性的蛋白质也可以改变阿尔茨海默氏淀粉样前体蛋白（APP）的加工。最初在造血细胞中鉴定，FKBP 52在神经元中表达丰富得多，包括海马、额叶皮质和基底神经节。鉴于高分子量亲免素FKBP 52在阿尔茨海默病易感的CNS区域高度表达的事实，我们研究了其在Aβ毒性中的作用。为了实现这一目标，我们产生了携带FKBP 52功能获得或功能丧失突变的Aβ转基因果蝇。FKBP 52过表达降低了Aβ的毒性并增加了Aβ果蝇的寿命，而FKBP 52功能丧失则加剧了这些Aβ表型。有趣的是，铜转运蛋白Atox 1（与FKBP 52相互作用）和Ctr 1A的突变增强了Aβ病理学，并在以铜螯合剂饮食饲养的FKBP 52突变果蝇中受到抑制。使用哺乳动物培养物，我们发现FKBP 52（−/−）细胞具有增加的细胞内铜和更高水平的Aβ。这种作用通过FKBP 52的重建而逆转。最后，我们还发现FKBP 52通过其FK 506相互作用结构域与APP形成稳定的复合物。总之，这些研究确定了FKBP 52在调节Aβ肽毒性中的新作用。
FK506 binding proteins (FKBPs), also called immunophilins, are prolyl-isomerases (PPIases) that participate in a wide variety of cellular functions including hormone signaling and protein folding. Recent studies indicate that proteins that contain PPIase activity can also alter the processing of Alzheimer's Amyloid Precursor Protein (APP). Originally identified in hematopoietic cells, FKBP52 is much more abundantly expressed in neurons, including the hippocampus, frontal cortex, and basal ganglia. Given the fact that the high molecular weight immunophilin FKBP52 is highly expressed in CNS regions susceptible to Alzheimer's, we investigated its role in Aβ toxicity. Towards this goal, we generated Aβ transgenic Drosophila that harbor gain of function or loss of function mutations of FKBP52. FKBP52 overexpression reduced the toxicity of Aβ and increased lifespan in Aβ flies, whereas loss of function of FKBP52 exacerbated these Aβ phenotypes. Interestingly, the Aβ pathology was enhanced by mutations in the copper transporters Atox1, which interacts with FKBP52, and Ctr1A and was suppressed in FKBP52 mutant flies raised on a copper chelator diet. Using mammalian cultures, we show that FKBP52 (−/−) cells have increased intracellular copper and higher levels of Aβ. This effect is reversed by reconstitution of FKBP52. Finally, we also found that FKBP52 formed stable complexes with APP through its FK506 interacting domain. Taken together, these studies identify a novel role for FKBP52 in modulating toxicity of Aβ peptides.
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FlyBase：十几个基因组。
影响因子：
14.9
作者：
Crosby MA;Goodman JL;Strelets VB;Zhang P;Gelbart WM;FlyBase Consortium
通讯作者：
FlyBase Consortium
DOI：
10.1111/j.1460-9568.2009.06701.x
发表时间：
2009-04
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Rival T;Page RM;Chandraratna DS;Sendall TJ;Ryder E;Liu B;Lewis H;Rosahl T;Hider R;Camargo LM;Shearman MS;Crowther DC;Lomas DA
通讯作者：
Lomas DA
影响因子：
56.9
作者：
Bose, S;Weikl, T;Buchner, J
通讯作者：
Buchner, J
影响因子：
3.3
作者：
Cao, Weihuan;Song, Ho-Juhn;Konsolaki, Mary
通讯作者：
Konsolaki, Mary
影响因子：
4.8
作者：
Gaburjakova, M;Gaburjakova, J;Marks, AR
通讯作者：
Marks, AR