A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death.
A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death.
复制标题
DOI：
10.1016/j.cell.2009.01.038
复制
发表时间：
2009-04-03
期刊：
影响因子：
64.5
通讯作者：
Glass CK
中科院分区：
文献类型：
--
作者：
Saijo K;Winner B;Carson CT;Collier JG;Boyer L;Rosenfeld MG;Gage FH;Glass CK
Nurr 1是一种孤儿核受体，在大脑中多巴胺能神经元的产生和维持中起着重要作用。Nurr 1的罕见突变与家族性帕金森病相关，但这种关系的基础尚未建立。在这里，我们表明，Nurr 1出乎意料地发挥作用，抑制小胶质细胞和星形胶质细胞中的促炎性神经毒性介质的表达。Nurr 1表达减少会导致小胶质细胞中的炎症反应过度，并被星形胶质细胞进一步放大，导致产生导致酪氨酸羟化酶表达神经元死亡的因子。Nurr 1通过与靶炎症基因启动子上的NF-κB-p65以信号依赖的方式对接发挥抗炎作用。随后，Nurr 1募集CoREST辅阻遏物复合物，导致NF-κB-p65的清除和转录抑制。这些研究表明，Nurr 1通过限制小胶质细胞和星形胶质细胞产生神经毒性介质来保护帕金森病中多巴胺能神经元的损失。
Nurr1, an orphan nuclear receptor, plays an essential role in the generation and maintenance of dopaminergic neurons in the brain. Rare mutations in Nurr1 are associated with familial Parkinson’s disease, but the underlying basis for this relationship has not been established. Here, we demonstrate that Nurr1 unexpectedly functions to inhibit expression of pro-inflammatory neurotoxic mediators in both microglia and astrocytes. Reduced Nurr1 expression results in exaggerated inflammatory responses in microglia that are further amplified by astrocytes, leading to the production of factors that cause death of tyrosine hydroxylase-expressing neurons. Nurr1 exerts anti-inflammatory effects by docking to NF-κB-p65 on target inflammatory gene promoters in a signal-dependent manner. Subsequently, Nurr1 recruits the CoREST corepressor complex, resulting in clearance of NF-κB-p65 and transcriptional repression. These studies suggest that Nurr1 protects against loss of dopaminergic neurons in Parkinson’s disease in part by limiting the production of neurotoxic mediators by microglia and astrocytes.
登录
查看更多内容
影响因子：
64.5
作者：
Ballas, N;Grunseich, C;Mandel, G
通讯作者：
Mandel, G
影响因子：
30.8
作者：
Le, WD;Xu, PY;Vassilatis, DK
通讯作者：
Vassilatis, DK
影响因子：
4.8
作者：
Buss, H;Dörrie, A;Kracht, M
通讯作者：
Kracht, M
影响因子：
3.9
作者：
Brown, G. C.
通讯作者：
Brown, G. C.
DOI：
10.1161/01.atv.0000238346.84458.5d
发表时间：
2006-10-01
影响因子：
8.7
作者：
Bonta, Peter I.;van Tiel, Claudia M.;de Vries, Carlie J. M.
通讯作者：
de Vries, Carlie J. M.