σ2R/TMEM97 in Retinal Ganglion Cell Degeneration

Abstract

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.

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“…We discovered that intravitreal (IVT) delivery of DKR-1677 (Figure 6A) prior to RIR injury, which was induced by a sudden increase in intraocular pressure, significantly protects RGCs (Figure 15). 60 This finding is the first to show that targeting σ 2 R/TMEM97 in the retina has neuroprotective effects on RGCs and might represent a new approach to preventative treatment of certain retinal degenerative conditions that lead to blindness.…”

“…We found that UKH-1114 and several other σ 2 R/TMEM97 ligands increase the survival of neurons in an assay in which primary murine cortical neurons are transfected with 586 N-terminal amino acids of the huntingtin protein bearing an 82 polyglutamine (Q) expansion (i.e., Htt N586 82Q) versus cells transfected with Htt N586 22Q (Figure 14A). 59 Interestingly, DKR-1677, which is neuroprotective in other animal models, 4,60 does not prolong survival. Cell morphology was analyzed by cotransfecting these neurons with green fluorescent protein (GFP), and nuclei were stained with Hoechst (Figure 14B).…”