The cyclic AMP cascade is altered in the fragile X nervous system.
The cyclic AMP cascade is altered in the fragile X nervous system.
复制标题
脆弱的X神经系统中的环状AMP级联反应发生了变化。
DOI：
10.1371/journal.pone.0000931
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发表时间：
2007-09-26
期刊：
影响因子：
3.7
通讯作者：
Bhattacharyya A
中科院分区：
文献类型：
--
作者：
Kelley DJ;Davidson RJ;Elliott JL;Lahvis GP;Yin JC;Bhattacharyya A
脆性X染色体综合征（FX）是一种发育障碍，以身体、认知和行为缺陷为特征，是智力迟钝和自闭症最常见的遗传原因。FX是由fmr1基因的三核苷酸扩增突变引起的，该突变降低了脆性X智力迟钝蛋白（FMRP）的水平。虽然研究工作集中在FMRP对mGluR信号传导的影响上，但FMRP的缺失如何导致FX的个体症状尚不清楚。先前对人类FX血细胞的研究显示环腺苷3′，5′-单磷酸（cAMP）级联发生改变。我们使用三种不同的模型系统测试了cAMP信号在FX神经系统中被改变的假设。fmr1基因敲除小鼠的血小板和大脑中cAMP的诱导水平显著降低。在人类FX神经细胞中，循环AMP的诱导也显著降低。此外，在FX果蝇的头部中cAMP的产生减少，这种缺陷可以通过重新引入dfmr基因来挽救。我们的研究结果表明，FX中cAMP产生的一个强大缺陷在物种间是保守的，并表明cAMP代谢可能作为人类疾病群体中有用的生物标志物。cAMP诱导减少对FX和自闭症谱系障碍的潜在原因有影响。已知调节cAMP级联的药物可能对FX患者有治疗作用，可以在这些模型中进行测试，从而补充当前以mGluR信号传导为中心的研究。
Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3′, 5′-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling.
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影响因子：
56.9
作者：
KREMER, EJ;PRITCHARD, M;RICHARDS, RI
通讯作者：
RICHARDS, RI
DOI：
10.1073/pnas.1834280100
发表时间：
2003-09-02
影响因子：
11.1
作者：
Bourtchouladze, R;Lidge, R;Tully, T
通讯作者：
Tully, T
影响因子：
16.2
作者：
McBride, SMJ;Choi, CH;Jongens, TA
通讯作者：
Jongens, TA
DOI：
10.1002/ajmg.1320450120
发表时间：
1993-01-01
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
BERRYKRAVIS, E;SKLENA, P
通讯作者：
SKLENA, P
影响因子：
3.6
作者：
BERRYKRAVIS, E;HICAR, M;CIURLIONIS, R
通讯作者：
CIURLIONIS, R