Parkin and Endoplasmic Reticulum Stress
Parkin and Endoplasmic Reticulum Stress
复制标题
帕金和内质网应激
DOI：
10.1111/j.1749-6632.2003.tb07467.x
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发表时间：
2003
影响因子：
5.2
通讯作者：
Y. Mizuno
中科院分区：
文献类型：
--
作者：
R. Takahashi;Y. Imai;N. Hattori;Y. Mizuno
翻译后摘要：常染色体隐性遗传青少年帕金森综合征（AR-JP）是由parkin基因突变引起的。帕金蛋白的特征在于其NH 2末端的泛素样结构域和其COOH末端的两个RING指基序和一个IBR（在RING指之间）基序（RING-IBR-RING）。我们发现帕金蛋白是一种E3泛素连接酶，它通过其RING-IBR-RING基序与泛素缀合酶（E2）结合。因此，假设AR-JP的发病机制是未识别的神经毒性蛋白（parkin的底物）的蓄积。在此假设的基础上，使用酵母双杂交系统寻找帕金的底物。一种假定的G蛋白偶联跨膜多肽，命名为Pael（parkin相关内皮素受体样）受体，被鉴定为parkin结合蛋白。当在细胞中过度表达时，这种受体倾向于变得未折叠、不溶性和泛素化。不溶性Pael受体导致内质网（ER）应激诱导的细胞死亡。Parkin在ER驻留E2存在下特异性泛素化该受体，并促进未折叠Pael受体的降解，从而抑制由ER中未折叠Pael受体积累诱导的细胞死亡。此外，Pael受体的不溶性形式在AR-JP患者的脑中积累。这种蛋白质在黑质的多巴胺能神经元中高度表达，这在帕金森病中特别受影响;尽管它也在纤维束中的少突胶质细胞中广泛表达。总之，我们发现未折叠Pael受体（parkin的底物）的积累可能导致AR-JP中多巴胺能神经元的选择性死亡。
Abstract: Autosomal‐recessive juvenile parkinsonism (AR‐JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin‐like domain at its NH2 terminus and by two RING finger motifs and one IBR (in between RING finger) motif at its COOH‐terminus (RING‐IBR‐RING). We showed that the parkin protein is an E3 ubiquitin ligase, which binds to ubiquitin‐conjugating enzymes (E2s) through its RING‐IBR‐RING motif. The pathogenesis of AR‐JP, therefore, was hypothesized to be accumulation of unidentified neurotoxic protein (a substrate of parkin). On the basis of this hypothesis, the substrate of parkin was sought using a yeast two‐hybrid system. A putative G protein‐coupled transmembrane polypeptide, named Pael (parkin‐associated endothelin receptor‐like) receptor, was identified as a parkin binding protein. When overexpressed in cells, this receptor tends to become unfolded, insoluble, and ubiquitinated. The insoluble Pael receptor leads to endoplasmic reticulum (ER) stress‐induced cell death. Parkin specifically ubiquitinates this receptor in the presence of ER‐resident E2s and promotes the degradation of unfolded Pael receptor, resulting in suppression of the cell death induced by the accumulation of unfolded Pael receptor in the ER. Moreover, the insoluble form of Pael receptor accumulates in the brain of AR‐JP patients. This protein is highly expressed in the dopaminergic neurons in the substantia nigra, which is specifically affected in Parkinson's disease; although it is also widely expressed in oligodendroglias in the fiber tract. In conclusion, we showed that the accumulation of unfolded Pael receptor (a substrate of parkin) may cause selective death of dopaminergic neurons in AR‐JP.
DOI：
10.1073/pnas.240347797
发表时间：
2000-11-21
影响因子：
11.1
作者：
Zhang, Y;Gao, J;Dawson, TM
通讯作者：
Dawson, TM