Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice.
Overexpression of optineurin E50K disrupts Rab8 interaction and leads to a progressive retinal degeneration in mice.
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DOI：
10.1093/hmg/ddq146
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发表时间：
2010-07-01
影响因子：
3.5
通讯作者：
Iwata T
中科院分区：
文献类型：
--
作者：
Chi ZL;Akahori M;Obazawa M;Minami M;Noda T;Nakaya N;Tomarev S;Kawase K;Yamamoto T;Noda S;Sasaoka M;Shimazaki A;Takada Y;Iwata T
青光眼是影响全球近800万人的双侧失明的主要原因之一。青光眼的特征在于视网膜神经节细胞（RGC）的进行性丧失，并且通常与眼内压（IOP）升高相关。然而，患有正常眼压性青光眼（NTG）（原发性开角型青光眼（POAG）的一种亚型）的患者发展为无IOP升高的疾病。导致NTG和POAG病理的分子途径仍不清楚。在这里，我们描述了过表达野生型（Wt）或突变的视神经磷酸酶（Optn）的转基因小鼠的表型特征。使用缺失第一（氨基酸153-174）或第二（氨基酸426-461）亮氨酸拉链的突变E50 K、H486 R和Optn进行过表达。16个月后，仅在E50 K突变小鼠的视网膜中观察到组织学异常，在正常IOP下，RGC和周边视网膜中的连接突触的损失导致视神经乳头处的神经纤维层变薄。E50 K小鼠还显示出整个视网膜的大量凋亡和变性，导致视网膜厚度减少约28%。在分子水平上，E50 K突变的引入破坏了Optn和Rab 8 GTf 3之间的相互作用，Rab 8 GTf 3是一种参与调节囊泡从高尔基体转运到质膜的蛋白质。Wt Optn和Rab 8复合物的活性GTP结合形式定位于高尔基复合体。这些数据表明，Optn序列的改变可以引发小鼠明显的视网膜变性。
Glaucoma is one of the leading causes of bilateral blindness affecting nearly 8 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) and is often associated with elevated intraocular pressure (IOP). However, patients with normal tension glaucoma (NTG), a subtype of primary open-angle glaucoma (POAG), develop the disease without IOP elevation. The molecular pathways leading to the pathology of NTG and POAG are still unclear. Here, we describe the phenotypic characteristics of transgenic mice overexpressing wild-type (Wt) or mutated optineurin (Optn). Mutations E50K, H486R and Optn with a deletion of the first (amino acids 153–174) or second (amino acids 426–461) leucine zipper were used for overexpression. After 16 months, histological abnormalities were exclusively observed in the retina of E50K mutant mice with loss of RGCs and connecting synapses in the peripheral retina leading to a thinning of the nerve fiber layer at the optic nerve head at normal IOP. E50K mice also showed massive apoptosis and degeneration of entire retina, leading to approximately a 28% reduction of the retina thickness. At the molecular level, introduction of the E50K mutation disrupts the interaction between Optn and Rab8 GTPase, a protein involved in the regulation of vesicle transport from Golgi to plasma membrane. Wt Optn and an active GTP-bound form of Rab8 complex were localized at the Golgi complex. These data suggest that alternation of the Optn sequence can initiate significant retinal degeneration in mice.
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影响因子：
15.9
作者：
Harada, Takayuki;Harada, Chikako;Tanaka, Kohichi
通讯作者：
Tanaka, Kohichi
影响因子：
56.9
作者：
Rezaie, T;Child, A;Sarfarazi, M
通讯作者：
Sarfarazi, M
影响因子：
6
作者：
Park, Bum-Chan;Shen, Xiang;Yue, Beatrice Y. J. T.
通讯作者：
Yue, Beatrice Y. J. T.
影响因子：
4.1
作者：
Foster, PJ;Buhrmann, R;Johnson, GJ
通讯作者：
Johnson, GJ
影响因子：
4.4
作者：
Leung, YF;Fan, BJ;Pang, CP
通讯作者：
Pang, CP