Immunohistochemical localization of a ubiquitin ligase HRD1 in murine brain
Immunohistochemical localization of a ubiquitin ligase HRD1 in murine brain
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DOI：
10.1002/jnr.21616
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发表时间：
2008-05-15
影响因子：
4.2
通讯作者：
Nomura, Yasuyuki
中科院分区：
文献类型：
--
作者：
Omura, Tomohiro;Kaneko, Masayuki;Nomura, Yasuyuki
Hrd1是一种E3泛素连接酶，在内质网相关降解(ERAD)中发挥重要作用。Parkin相关内皮素受体样受体(PAEL-R)是E3泛素连接酶PARKIN的底物，参与了常染色体隐性遗传性青少年帕金森综合征(AR-JP)患者内质网应激诱导的多巴胺神经元细胞死亡。最近，我们发现内源性Hrd1与PAEL-R相互作用，并且Hrd1促进PAEL-R的降解，保护由PAEL-R积聚引起的细胞死亡。另一个研究小组最近报道，Hrd1抑制多谷氨酰胺扩张的亨廷顿蛋白的毒性。然而，Hrd1蛋白在大脑中的定位尚不清楚，尤其是与神经退行性疾病相关的。在本研究中，我们用免疫组织化学方法对Hrd1在脑内的定位进行了研究，结果表明，Hrd1在含有多巴胺能神经元的黑质致密部广泛表达，在大脑皮层、海马、齿状回、纹状体、苍白球和小脑皮层的Purkinje细胞也有表达。此外，Hrd1免疫反应在神经细胞中表达，而在神经胶质细胞中不表达。这些结果表明，Hrd1可能在维持较高的大脑功能方面发挥重要作用，包括运动功能或学习和记忆。此外，Hrd1可能含有与神经退行性疾病有关的PAEL-R以外的底物。(C)2008年Wiley-Liss，Inc.
HRD1 is an E3 ubiquitin ligase and plays an important role in endoplasmic reticulum-associated degradation (ERAD). Parkin-associated endothelin receptor-like receptor (Pael-R) is a substrate of the E3 ubiquitin ligase parkin, which has been implicated in ER stress-induced cell death in dopamine neurons in autosomal recessive juvenile parkinsonism (AR-JP). Recently, we demonstrated that endogenous HRD1 interacts with Pael-R, and that HRD1 promotes the degradation of Pael-R and protects cell death caused by the accumulation of Pael-R. Another group recently reported that HRD1 suppresses the toxicity of polyglutamine-expanded huntingtin. However, the topographical localization of HRD1 protein in the brain, especially related to neurodegenerative disease, is unclear. In this study, we used immunohistochemistry to investigate the topographical localization of HRD1 in the brain and demonstrated that HRD1 immunoreactivity was expressed widely in the substantia nigra pars compacta (SNC) containing dopaminergic neurons and was expressed in the cerebral cortex, hippocampus, dentate gyrus, striatum, globus pallidus, and Purkinje cells of the cerebellar cortex. Furthermore, HRD1 immunoreactivity was detected in the neuronal cells but not in the glial cells. These results suggest that HRD1 may play an important role in maintaining higher brain function, including motor function or learning and memory. In addition, HRD1 may have substrates other than Pael-R that are implicated in neurodegenerative disorders. (c) 2008 Wiley-Liss, Inc.