Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease
Chronic overexpression of the calcineurin inhibitory gene DSCR1 (Adapt78) is associated with Alzheimer's disease
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DOI：
10.1074/jbc.m102829200
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发表时间：
2001-10-19
影响因子：
4.8
通讯作者：
Davies, KJA
中科院分区：
文献类型：
--
作者：
Ermak, G;Morgan, TE;Davies, KJA
DSCR 1（Adapt 78）基因被独立地发现为“唐氏综合征候选区域”的居民，并作为在氧化应激期间瞬时诱导的“适应性反应”休克或应激基因。最近发现DSCR 1（Adapt 78）基因产物是丝氨酸/苏氨酸磷酸酶、钙调神经磷酸酶及其信号通路的抑制剂。我们假设DSCR 1（Adapt 78）也可能参与阿尔茨海默病的发展。为了解决这个问题，我们首先研究了DSCR 1（Adapt 78）在多种人体组织中的表达，发现在脑、脊髓、肾、肝、乳腺、骨骼肌和心脏中有显著表达。在脑内，DSCR 1（Adapt 78）主要在大脑皮层、海马、黑质、丘脑和延髓内的神经元中表达。当我们比较阿尔茨海默病患者和未确诊阿尔茨海默病的死亡个体的死后大脑样本中DSCR 1（Adapt 78）mRNA的表达时，我们发现年龄匹配的阿尔茨海默病患者的DSCR 1（Adapt 78）mRNA水平约为对照组的两倍。DSCR 1（Adapt 78）mRNA水平实际上是广泛神经元缠结（阿尔茨海默病的标志）患者的三倍。相比之下，唐氏综合症患者（患有阿尔茨海默氏症）的死后大脑样本也显示出DSCR 1（Adapt 78）mRNA水平比对照组高出两到三倍。使用细胞培养模型，我们发现淀粉样蛋白β（1-42）肽，这是阿尔茨海默氏症中老年斑的主要成分，可以直接诱导DSCR 1（Adapt 78）表达的增加。我们的发现将DSCR 1（Adapt 78）与阿尔茨海默病的主要标志如淀粉样蛋白、老年斑和神经元缠结联系起来。
The DSCR1 (Adapt78) gene was independently discovered as a resident of the "Down syndrome candidate region" and as an "adaptive response" shock or stress gene that is transiently induced during oxidative stress. Recently the DSCR1 (Adapt78) gene product was discovered to be an inhibitor of the serine/threonine phosphatase, calcineurin, and its signaling pathways. We hypothesized that DSCR1 (Adapt78) might also be involved in the development of Alzheimer's disease. To address this question we first studied DSCR1 (Adapt78) in multiple human tissues and found significant expression in brain, spinal cord, kidney, liver, mammary gland, skeletal muscle, and heart. Within the brain DSCR1 (Adapt78) is predominantly expressed in neurons within the cerebral cortex, hippocampus, substantia nigra, thalamus, and medulla oblongata. When we compared DSCR1 (Adapt78) mRNA expression in post-mortem brain samples from Alzheimer's disease patients and individuals who had died with no Alzheimer's diagnosis, we found that DSCR1 (Adapt78) mRNA levels were about twice as high in age-matched Alzheimer's patients as in controls. DSCR1 (Adapt78) mRNA levels were actually three times higher in patients with extensive neurofibrillary tangles (a hallmark of Alzheimer's disease) than in controls. In comparison, postmortem brain samples from Down syndrome patients (who suffer Alzheimer's symptoms) also exhibited DSCR1 (Adapt78) mRNA levels two to three times higher than controls. Using a cell culture model we discovered that the amyloid beta (1-42) peptide, which is a major component of senile plaques in Alzheimer's, can directly induce increased expression of DSCR1 (Adapt78). Our findings associate DSCR1 (Adapt78) with such major hallmarks of Alzheimer's disease as amyloid protein, senile plaques, and neurofibrillary tangles.