Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration.
Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration.
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DOI：
10.1186/s13024-018-0250-z
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发表时间：
2018-04-04
影响因子：
15.1
通讯作者：
Zhang SX
中科院分区：
文献类型：
--
作者：
McLaughlin T;Falkowski M;Park JW;Keegan S;Elliott M;Wang JJ;Zhang SX
衰老是神经退行性疾病的最大风险因素，年龄延长导致神经元变性和视觉系统功能下降。在与年龄相关的神经元退化的许多促成因素中，是响应于细胞应激的内质网（ER）中的未折叠蛋白反应（UPR）的活化不足。X-box binding protein 1（X-box binding protein 1，XBP 1）是UPR的主要组成部分，对维持蛋白质稳态和减少细胞应激至关重要。在此，我们研究了在成年期和衰老的早期阶段，XBP 1在维持视网膜神经元形态和功能完整性中的作用。在年轻成年和老年小鼠中测量视网膜中的XBP 1活化的基础和诱导水平。视网膜神经元中XBP 1的条件性敲除（cKO）通过将XBP 1 floxed小鼠与视网膜特异性Cre重组酶系（Chx 10-Cre）杂交来实现。视网膜形态学，神经元群体，包括光感受器，双极细胞，视网膜神经节细胞（RGCs），突触结构，和小胶质细胞的激活进行了检查与免疫组织化学和染色的视网膜切片。视网膜功能评价与光适应（明视）和暗适应（暗视）视网膜电图。采用Seahorse XFe 24细胞外液通量分析仪检测视网膜线粒体功能和代谢。老年野生型（WT）小鼠的视网膜显示Xbp 1 s的基础水平显著降低，ER应激反应的激活受损。在XBP 1 cKO小鼠中，在12-14月龄时观察到视网膜层变薄和RGC丢失所证明的视网膜显著结构变性，以及明视和暗视ERG b波减弱所指示的功能缺陷。此外，在XBP 1 cKO视网膜中发现了与激活的小胶质细胞共定位的不连续和混乱的突触板层。此外，cKO小鼠表现出双极细胞和光感受器之间的异位突触显著增加，这与20-24月龄的WT小鼠惊人地相似。这些变化与视网膜糖酵解缺陷相关，而线粒体呼吸功能在cKO视网膜中表现正常。12-14月龄的XBP 1 cKO小鼠表现出显著的结构、功能和代谢缺陷，与两倍于该年龄的WT小鼠非常相似。我们的研究结果表明，XBP 1的缺乏，UPR的一个关键组成部分，加速了年龄相关的视网膜神经变性。本文的在线版本（10.1186/s13024-018-0250-z）包含补充材料，可供授权用户使用。
Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging. The basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10-Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer. The retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12–14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20–24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina. XBP1 cKO mice at 12–14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration. The online version of this article (10.1186/s13024-018-0250-z) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
7.8
作者：
Martínez G;Duran-Aniotz C;Cabral-Miranda F;Vivar JP;Hetz C
通讯作者：
Hetz C
影响因子：
6.2
作者：
Streit, WJ;Sammons, NW;Sparks, DL
通讯作者：
Sparks, DL
影响因子：
2.7
作者：
Rowan, S;Cepko, CL
通讯作者：
Cepko, CL
DOI：
10.1073/pnas.1002575107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Henis-Korenblit, Sivan;Zhang, Peichuan;Kenyon, Cynthia
通讯作者：
Kenyon, Cynthia