σR/TMEM97 in retinal ganglion cell degeneration.

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