Absence of sigma 1 receptor accelerates photoreceptor cell death in a murine model of retinitis pigmentosa

Jing Wang, Alan B Saul, Xuezhi Cui, Penny Roon, Sylvia B Smith

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4545-4558
Number of pages14
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number11
DOIs
StatePublished - Sep 1 2017

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Photoreceptor Cells
Retinitis Pigmentosa
Cell Death
Endoplasmic Reticulum Stress
Gliosis
Optical Coherence Tomography
sigma-1 receptor
Peanut Agglutinin
Retinal Neurons
Unfolded Protein Response
Retinal Diseases
Heat-Shock Proteins
Ganglia
Neurodegenerative Diseases
Retina

Keywords

  • Cones
  • ERG
  • Retinal degeneration
  • Retinal neuroprotection
  • Rods
  • rd10 mouse

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Absence of sigma 1 receptor accelerates photoreceptor cell death in a murine model of retinitis pigmentosa. / Wang, Jing; Saul, Alan B; Cui, Xuezhi; Roon, Penny; Smith, Sylvia B.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 11, 01.09.2017, p. 4545-4558.

Research output: Contribution to journalArticle

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AU - Saul, Alan B

AU - Cui, Xuezhi

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AU - Smith, Sylvia B

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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

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KW - Retinal neuroprotection

KW - Rods

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