REEP6 deficiency leads to retinal degeneration through disruption of ER homeostasis and protein trafficking.
REEP6 deficiency leads to retinal degeneration through disruption of ER homeostasis and protein trafficking.
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DOI：
10.1093/hmg/ddx149
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发表时间：
2017-07-15
影响因子：
3.5
通讯作者：
Cheetham ME
中科院分区：
文献类型：
--
作者：
Agrawal SA;Burgoyne T;Eblimit A;Bellingham J;Parfitt DA;Lane A;Nichols R;Asomugha C;Hayes MJ;Munro PM;Xu M;Wang K;Futter CE;Li Y;Chen R;Cheetham ME
色素性视网膜炎（RP）是遗传性视网膜营养不良的最常见形式。我们最近在几个常染色体隐性 RP 家族中发现了 REEP6 的突变，REEP6 编码受体表达增强蛋白 6。 REEP6 与 ER 成形蛋白和潜在受体辅助蛋白的 REEP 和 Yop1p 家族相关，但 REEP6 在视网膜中的作用尚不清楚。在这里，我们使用 CRISPR/Cas9 基因编辑产生的 Reep6 敲除小鼠来描述与 REEP6 功能丧失相关的疾病机制。在对照小鼠中，REEP6 定位于视杆光感受器的内节和外丛状层。 Reep6-/-小鼠从P20开始表现出进行性光感受器变性。通过透射电子显微镜和 3View 串行块面扫描电镜对 P20 进行的超微结构分析显示 Reep6-/- 杆中远端 ER 的扩张以及线粒体数量的增加。视网膜电图显示光感受器功能障碍先于退化，表明光转导存在潜在缺陷。对视紫红质、Rom1 或外周蛋白/rds 的运输没有影响；然而，视网膜鸟苷酸环化酶GC1和GC2在Reep6敲除动物中受到严重影响，几乎检测不到表达。这些变化与 C/EBP 同源蛋白 (CHOP) 表达的增加和 caspase 12 的激活相关，表明 ER 应激导致细胞死亡。总的来说，这些数据表明 REEP6 通过促进鸟苷酸环化酶的稳定性和/或运输以及维持 ER 和线粒体稳态，在维持 cGMP 稳态中发挥重要作用。
Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy. We recently identified mutations in REEP6, which encodes the receptor expression enhancing protein 6, in several families with autosomal recessive RP. REEP6 is related to the REEP and Yop1p family of ER shaping proteins and potential receptor accessory proteins, but the role of REEP6 in the retina is unknown. Here we characterize the disease mechanisms associated with loss of REEP6 function using a Reep6 knockout mouse generated by CRISPR/Cas9 gene editing. In control mice REEP6 was localized to the inner segment and outer plexiform layer of rod photoreceptors. The Reep6-/- mice exhibited progressive photoreceptor degeneration from P20 onwards. Ultrastructural analyses at P20 by transmission electron microscopy and 3View serial block face scanning EM revealed an expansion of the distal ER in the Reep6-/- rods and an increase in their number of mitochondria. Electroretinograms revealed photoreceptor dysfunction preceded degeneration, suggesting potential defects in phototransduction. There was no effect on the traffic of rhodopsin, Rom1 or peripherin/rds; however, the retinal guanylate cyclases GC1 and GC2 were severely affected in the Reep6 knockout animals, with almost undetectable expression. These changes correlated with an increase in C/EBP homologous protein (CHOP) expression and the activation of caspase 12, suggesting that ER stress contributes to cell death. Collectively, these data suggest that REEP6 plays an essential role in maintaining cGMP homeostasis though facilitating the stability and/or trafficking of guanylate cyclases and maintaining ER and mitochondrial homeostasis.
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影响因子：
3.5
作者：
Eblimit, Aiden;Nguyen, Thanh-Minh T.;Chen, Rui
通讯作者：
Chen, Rui
DOI：
10.1007/978-3-319-17121-0_25
发表时间：
2016-01-01
期刊：
RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY
影响因子：
--
作者：
Chiang, Wei-Chieh;Joseph, Victory;Lin, Jonathan H.
通讯作者：
Lin, Jonathan H.
DOI：
10.1007/978-3-319-17121-0_30
发表时间：
2016-01-01
期刊：
RETINAL DEGENERATIVE DISEASES: MECHANISMS AND EXPERIMENTAL THERAPY
影响因子：
--
作者：
Lobo, Glenn P.;Ebke, Lindsey A.;Hagstrom, Stephanie A.
通讯作者：
Hagstrom, Stephanie A.
影响因子：
9.8
作者：
Beetz, Christian;Pieber, Thomas R.;Auer-Grumbach, Michaela
通讯作者：
Auer-Grumbach, Michaela
影响因子：
3.5
作者：
Athanasiou D;Aguilà M;Bevilacqua D;Novoselov SS;Parfitt DA;Cheetham ME
通讯作者：
Cheetham ME