σ2R/TMEM97 in retinal ganglion cell degeneration
Hua Wang, Zhiyou Peng, Yiwen Li, James J. Sahn, Timothy R. Hodges, Tsung‐Han Chou, Qiong Liu, Xuezhi Zhou, Shuliang Jiao, Vittorio Porciatti, Daniel J. Liebl, Stephen F. Martin, Rong Wen
Abstract
Abstract The sigma 2 receptor (σ 2 R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ 2 R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ 2 R/TMEM97 in neurodegenerative processes. To understand the function of σ 2 R/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 σ 2 R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ 2 R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ 2 R/TMEM97 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 for RGC degenerative diseases by inhibiting σ 2 R/TMEM97.