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σ2R/TMEM97 in retinal ganglion cell degeneration

Wang, Hua, Peng, Zhiyou, Li, Yiwen, Sahn, James J., Hodges, Timothy R., Chou, Tsung-Han, Liu, Qiong, Zhou, Xuezhi, Jiao, Shuliang, Porciatti, Vittorio, Liebl, Daniel J., Martin, Stephen F., Wen, Rong·2022·Scientific Reports
DOI 10.1038/s41598-022-24537-3PMC PMC9715665
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Abstract

The sigma 2 receptor (σ 2 R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ 2 R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ 2 R/TMEM97 in neurodegenerative processes. To understand the function of σ 2 R/TMEM97 in neurodegeneration pathways, we characterized ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97−/− mice and found that RGCs in TMEM97−/− mice are resistant to degeneration. In addition, intravitreal injection of a selective σ 2 R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ 2 R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ 2 R/TMEM97 is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σ 2 R/TMEM97 in RGCs and likely in other σ 2 R/TMEM97 expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches for RGC degenerative diseases by inhibiting σ 2 R/TMEM97.

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  • In the retina, S2R is expressed in retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells.

    “In the retina, S2R is expressed in several cell types including the retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells [70,71,72,73,74].”

    From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [73]

  • S2R expression is elevated in retinal pigment epithelium-specific Clic4 knockout mice, which exhibit functional and pathological hallmarks of dry AMD; TMEM97 knockout mice have exhibited conflicting results in dry AMD models; and S2R-selective modulation with CM398 reduced photoreceptor loss and retinal autofluorescent granules in an illumination-induced AMD model.

    “S2R expression is elevated in retinal pigment epithelium-specific Clic4 knockout mice, which exhibit both functional and pathological hallmarks of dry AMD. Conversely, TMEM97 knockout mice have exhibited conflicting results in dry AMD models, which are likely dependent upon the type of stressor used to induce pathology. Intravenous administration of sodium iodate to TMEM97 knockout animals induced”

    From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [73]

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Metadata

Authors
Wang, H., Peng, Z., Li, Y., Sahn, J. J., Hodges, T. R., Chou, T.-H., Liu, Q., Zhou, X., Jiao, S., Porciatti, V., Liebl, D. J., Martin, S. F., & Wen, R.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2022-12-01
Volume
12
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-022-24537-3
PMC
PMC9715665
Cited by
13
References
4
Language
en
Licence
Funders
  • Hope For Vision (Grant)
  • Office of Extramural Research, National Institutes of Health (R01EY023666; R01EY026643; R01EY031492; P30EY14801; NS098740; NS120028;)
  • Miami Project to Cure Paralysis (Support)
  • Welch Foundation (F-0652)
  • Dell Medical School, University of Texas at Austin (Texas Health Catalyst program)

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