Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects
Altered mRNA Levels of Glucocorticoid Receptor, Mineralocorticoid Receptor, and Co-Chaperones (FKBP5 and PTGES3) in the Middle Frontal Gyrus of Autism Spectrum Disorder Subjects
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DOI：
10.1007/s12035-015-9178-2
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发表时间：
2016-05-01
影响因子：
5.1
通讯作者：
Pillai, Anilkumar
中科院分区：
文献类型：
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作者：
Patel, Neil;Crider, Amanda;Pillai, Anilkumar
虽然压力与自闭症谱系障碍（ASD）的病理生理学有关，但尚不清楚ASD受试者大脑中糖皮质激素受体（GR）水平是否发生改变。通过qRT-PCR检测了13例ASD和13例年龄匹配对照的死后额中回组织中GR亚型（GR α、GR β、GR γ和GRP）、盐皮质激素受体（MR）、GR辅助分子伴侣（FKBP 5、PTGES 3和BAG 1）和炎性细胞因子（IL-6、IL-1 β和IFN-γ）的信使RNA（mRNA）水平。Western blotting检测蛋白水平。我们发现，与对照组相比，ASD受试者中GR α（64%）、GR γ（48%）、GRP（20%）和MR（46%）mRNA水平显著降低。然而，在ASD受试者中观察到FKBP 5（42%）和PTGES 3（35%）mRNA水平的显著增加。与对照组相比，ASD受试者中GR β和BAG 1的mRNA水平没有差异。MR mRNA表达与发育异常诊断评分呈负相关。在蛋白质水平上，与对照组相比，ASD患者GR和MR显著降低，但FKBP 5和PTGES 3无变化。此外，我们观察到ASD受试者中IL-1 β和IFN-γ mRNA水平显著增加，这些细胞因子与GR水平呈负相关。我们的数据首次报道了ASD中GR、MR、FKBP 5和PTGES 3的调节异常，并提示炎症在ASD中GR功能改变中的可能作用。
Although stress has been implicated in the pathophysiology of autistic spectrum disorder (ASD), it is not known whether glucocorticoid receptor (GR) levels are altered in the brain of subjects with ASD. The messenger RNA (mRNA) levels of GR isoforms (GR alpha, GR beta, GR gamma, and GRP), mineralocorticoid receptor (MR), GR co-chaperones (FKBP5, PTGES3, and BAG1), and inflammatory cytokines (IL-6, IL-1 beta, and IFN-gamma) were examined in the postmortem middle frontal gyrus tissues of 13 ASD and 13 age-matched controls by qRT-PCR. The protein levels were examined by Western blotting. We found significant decreases in GR alpha (64 %), GR gamma (48 %), GRP (20 %) and MR (46 %) mRNA levels in ASD subjects as compared to controls. However, significant increases in FKBP5 (42 %) and PTGES3 (35 %) mRNA levels were observed in ASD subjects. There were no differences in the mRNA levels of GR beta and BAG1 in ASD subjects as compared to controls. MR mRNA was found to be negatively correlated with the diagnostic score for abnormality of development. On the protein level, significant reductions in GR and MR, but no change in FKBP5 and PTGES3 were found in ASD subjects as compared to controls. Moreover, we observed significant increases in IL-1 beta and IFN-gamma mRNA levels in ASD subjects, and these cytokines were negatively associated with GR levels. Our data, for the first time, reports dysregulation of GR, MR, FKBP5, and PTGES3 in ASD and suggest a possible role of inflammation in altered GR function in ASD.