Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa.
Absence of Sigma 1 Receptor Accelerates Photoreceptor Cell Death in a Murine Model of Retinitis Pigmentosa.
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DOI：
10.1167/iovs.17-21947
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发表时间：
2017-09-01
影响因子：
4.4
通讯作者：
Smith SB
中科院分区：
文献类型：
--
作者：
Wang J;Saul A;Cui X;Roon P;Smith SB
Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R−/− mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration. Wild-type, rd10, and rd10/Sig1R−/− mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels. Photopic ERG responses were reduced significantly in rd10/Sig1R−/− versus rd10 mice at P28 (31 ± 6 vs. 56 ± 7 μV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R−/− mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R−/− versus rd10 mice. rd10/Sig1R−/− mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R−/− versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R−/− mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R−/− mice versus rd10. Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R−/− than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival.
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影响因子：
17.8
作者：
Guadagni, Viviana;Novelli, Elena;Strettoi, Enrica
通讯作者：
Strettoi, Enrica
影响因子：
4.4
作者：
Jiang, Guoliang;Mysona, Barbara;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
影响因子：
2.5
作者：
Gargini, Claudia;Terzibasi, Eva;Strettoi, Enrica
通讯作者：
Strettoi, Enrica
影响因子：
3.5
作者：
DECOSTA, BR;BOWEN, WD;RICE, KC
通讯作者：
RICE, KC
影响因子：
4.4
作者：
Ha, Yonju;Saul, Alan;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.