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.

The sigma 2 receptor (σ2R) was recently identified as an ER (endoplasmic reticulum) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that compounds that bind to σ2R/TMEM97 are neuroprotective, suggesting that σ2R/TMEM97 is involved in pathways leading to neurodegeneration. We explore the role of σ2R/TMEM97 in neurodegeneration by characterizing ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97−/− mice and demonstrate that in the absence of σ2R/TMEM97, RGCs are resistant to degeneration. In addition, we show that DKR-1677, a selective σ2R/TMEM97 ligand, significantly protects RGCs from ischemia-induced degeneration in wildtype mice. These results provide conclusive evidence that σ2R/TMEM97 plays a significant role in RGC death to facilitate neurodegeneration following ischemic injury. Blocking the function of σ2R/TMEM97 thus 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 to treat RGC degenerative diseases by inhibiting σ2R/TMEM97.