TY - JOUR
T1 - Absence of sigma 1 receptor accelerates photoreceptor cell death in a murine model of retinitis pigmentosa
AU - Wang, Jing
AU - Saul, Alan
AU - Cui, Xuezhi
AU - Roon, Penny
AU - Smith, Sylvia B.
N1 - Funding Information:
Supported by grants from the National Institutes of Health (R01 EY014560) and The Foundation Fighting Blindness (TA-NMT-0617-0721-AUG). Disclosure: J. Wang, None; A. Saul, None; X. Cui, None; P. Roon, None; S.B. Smith, None
Publisher Copyright:
© 2017 The Authors.
PY - 2017/9
Y1 - 2017/9
N2 - PURPOSE. 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. METHODS. Wild-type, rd10, and rd10/Sig1R–/– mice were subjected to ERG and spectraldomain 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. RESULTS. 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. CONCLUSIONS. 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.
AB - PURPOSE. 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. METHODS. Wild-type, rd10, and rd10/Sig1R–/– mice were subjected to ERG and spectraldomain 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. RESULTS. 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. CONCLUSIONS. 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.
KW - Cones
KW - ERG
KW - Retinal degeneration
KW - Retinal neuroprotection
KW - Rods
KW - rd10 mouse
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U2 - 10.1167/iovs.17-21947
DO - 10.1167/iovs.17-21947
M3 - Article
C2 - 28877319
AN - SCOPUS:85029173858
VL - 58
SP - 4545
EP - 4558
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
SN - 0146-0404
IS - 11
ER -