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Abstract
The sigma 2 receptor (σ2R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ2R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ2R/TMEM97 in neurodegenerative processes. To understand the function of σ2R/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 σ2R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ2R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ2R/TMEM97 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 for RGC degenerative diseases by inhibiting σ2R/TMEM97.
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Details
1 Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606)
2 University of Texas at Austin, Department of Chemistry and Biochemistry, Austin, USA (GRID:grid.89336.37) (ISNI:0000 0004 1936 9924)
3 Florida International University, Department of Biomedical Engineering, Miami, USA (GRID:grid.65456.34) (ISNI:0000 0001 2110 1845)
4 University of Miami, Miller School of Medicine, Department of Neurosurgery, Miami, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606)