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