Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation.
Parkin targets NOD2 to regulate astrocyte endoplasmic reticulum stress and inflammation.
复制标题
作者：
Singh K;Han K;Tilve S;Wu K;Geller HM;Sack MN
黑质多巴胺能神经元的丧失导致帕金森病（PD）。退行性PD通常在70岁时出现，而遗传性疾病，包括PARK2突变，易患早发性PD。PARK2编码帕金E3泛素连接酶，其赋予对线粒体和细胞保真度的多效性效应，并作为内质网（ER）应激信号传导的介体。虽然大多数研究parkin的改善作用的研究集中在多巴胺能神经元，但我们发现星形胶质细胞富含parkin。此外，缺乏帕金蛋白的星形胶质细胞显示应激诱导的核苷酸寡聚化结构域受体2（NOD2）升高，NOD2是一种整合ER应激和炎症的胞质受体。考虑到星形胶质细胞的神经营养和免疫调节作用，我们推断parkin可能调节星形胶质细胞内质网应激和炎症以控制神经元稳态。我们发现，在响应ER应激，parkin敲低星形胶质细胞表现出夸张的ER应激，JNK激活和细胞因子释放，并减少神经营养因子的表达。在共培养研究中，我们证明多巴胺能SHSY5Y细胞和原代神经元与parkin耗尽的星形胶质细胞的存在下，更容易受到ER应激和炎症诱导的凋亡比野生型星形胶质细胞。帕金与NOD2相互作用，泛素化并降低NOD2水平。此外，帕金基因诱导改善了NOD2表达细胞的炎症，并在星形胶质细胞中敲低NOD2抑制了帕金缺陷星形胶质细胞的炎症缺陷，同时减弱了神经元凋亡。总的来说，这些数据确定了帕金在调节NOD2作为星形胶质细胞控制神经元稳态的调节节点中的作用。
Loss of substantia nigra dopaminergic neurons results in Parkinson disease (PD). Degenerative PD usually presents in the seventh decade whereas genetic disorders, including mutations in PARK2, predispose to early-onset PD. PARK2 encodes the parkin E3 ubiquitin ligase which confers pleotropic effects on mitochondrial and cellular fidelity and as a mediator of endoplasmic reticulum (ER) stress signaling. Although the majority of studies investigating ameliorative effects of parkin focus on dopaminergic neurons we found that astrocytes are enriched with parkin. Furthermore, astrocytes deficient in parkin display stress-induced elevation of nucleotide-oligomerization domain receptor 2 (NOD2), a cytosolic receptor integrating ER stress and inflammation. Given the neurotropic and immunomodulatory role of astrocytes we reasoned that parkin may regulate astrocyte ER stress and inflammation to control neuronal homeostasis. We show that, in response to ER stress, parkin knockdown astrocytes exhibit exaggerated ER stress, JNK activation and cytokine release, and reduced neurotropic factor expression. In coculture studied we demonstrate that dopaminergic SHSY5Y cells and primary neurons with the presence of parkin depleted astrocytes are more susceptible to ER stress and inflammation-induced apoptosis than wildtype astrocytes. Parkin interacted with, ubiquitylated and diminished NOD2 levels. Additionally, the genetic induction of parkin ameliorated inflammation in NOD2 expressing cells and knockdown of NOD2 in astrocytes suppressed inflammatory defects in parkin deficient astrocytes and concurrently blunted neuronal apoptosis. Collectively these data identify a role for parkin in modulating NOD2 as a regulatory node in astrocytic control of neuronal homeostasis.
登录
查看更多内容
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
DOI：
10.1073/pnas.1113248109
发表时间：
2012-04-17
影响因子：
11.1
作者：
Johnson, Bethann N.;Berger, Alison K.;LaVoie, Matthew J.
通讯作者：
LaVoie, Matthew J.
影响因子：
8.6
作者：
Banati, RB;Daniel, SE;Blunt, SB
通讯作者：
Blunt, SB
影响因子：
6.2
作者：
Gorina, Roser;Font-Nieves, Miriam;Planas, Anna M.
通讯作者：
Planas, Anna M.
影响因子：
64.8
作者：
Keestra-Gounder AM;Byndloss MX;Seyffert N;Young BM;Chávez-Arroyo A;Tsai AY;Cevallos SA;Winter MG;Pham OH;Tiffany CR;de Jong MF;Kerrinnes T;Ravindran R;Luciw PA;McSorley SJ;Bäumler AJ;Tsolis RM
通讯作者：
Tsolis RM