σ2R/TMEM97 in Retinal Ganglion Cell Degeneration

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