biostudies-literatureWang HDell Medical School, University of Texas at AustinMiami Project to Cure ParalysisOffice of Extramural Research, National Institutes of HealthWelch FoundationHope For Vision20753https://www.ebi.ac.uk/biostudies/studies/S-EPMC9715665biostudies-literatureUnknown12(1)The sigma 2 receptor (σ₂R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ₂R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ₂R/TMEM97 in neurodegenerative processes. To understand the function of σ₂R/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 σ₂R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ₂R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ₂R/TMEM97 is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σ₂R/TMEM97 in RGCs and likely in other σ₂R/TMEM97 expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches for RGC degenerative diseases by inhibiting σ₂R/TMEM97.Scientific reportsσ₂R/TMEM97 in retinal ganglion cell degeneration.PMC9715665GrantSupportR01EY023666; R01EY026643; R01EY031492; P30EY14801; NS098740; NS120028;F-0652Texas Health Catalyst programChou THMartin SFLiebl DJLiu QWang HWen RZhou XPeng ZLi YSahn JJJiao SPorciatti VHodges TRfalseσ₂R/TMEM97 in retinal ganglion cell degeneration.The sigma 2 receptor (σ₂R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ₂R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ₂R/TMEM97 in neurodegenerative processes. To understand the function of σ₂R/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 σ₂R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ₂R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ₂R/TMEM97 is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σ₂R/TMEM97 in RGCs and likely in other σ₂R/TMEM97 expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches for RGC degenerative diseases by inhibiting σ₂R/TMEM97.2022-01-01T00:00:00Z2022 Dec2025-04-25T17:09:23.389Z2025-04-06T05:03:42.597ZS-EPMC97156653645668610.1038/s41598-022-24537-3