σ2R/TMEM97 in retinal ganglion cell degeneration

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.

Highly specific σ2R/TMEM97 ligand alleviates neuropathic pain and inhibits the integrated stress response

“…It reduces axonal degeneration and provides dose-dependent enhancement of cognitive performance in the blast injury model of TBI, while it protects oligodendrocytes and cortical neurons in the controlled cortical impact model (19). DKR-1677 also protects retinal ganglion cells from ischemia/reperfusion injury (21). We demonstrate herein that SAS-0132 and DKR-1677 increase p-eIF2α expression in mouse DRG neurons, whereas FEM-1689 reduces p-eIF2α, suggesting that these compounds have distinct effects on the ISR.…”

“…TMEM97KO mice were donated by Dr. Liebl (University of Miami, Mouse Resource & Research Centers MMRRC, Tmem97 tm1(KOMP)Vlcg , stock #050147-UCD) (21). These mice were back crossed with C57BL/6 mice obtained from Charles River.…”

Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases

“…Consistent with a role of S2R in synapses and in Alzheimer’s disease [ 69 ], S2R (TMEM97) has been demonstrated using Förster resonance energy transfer to colocalize with amyloid-β in synaptic densities [ 65 ]. In the retina, S2R is expressed in several cell types including the retinal pigment epithelium cells, photoreceptors, and retinal ganglion cells [ 70 , 71 , 72 , 73 , 74 ].…”

“…While ongoing studies attempt to elucidate the functions of each protein, S2R, TMEM97, and PGRMC1 converge in co-localization/co-expression and their regulation of amyloid-β binding. References: (1) [ 80 , 81 ]; (2) [ 82 ]; (3) [ 5 , 63 , 67 , 73 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]; (4) [ 62 , 66 ]; (5) [ 51 , 91 , 92 ]; (6) [ 16 , 61 ]; (7) [ 61 , 93 , 94 ]; (8) [ 1 , 59 , 95 ]; (9) [ 2 , 3 , 96 ]; (10) [ 97 , 98 , 99 ]; (11) [ 100 ]; (12) [ 78 ]; (13) [ 101 , 102 ]; (14) [ 103 , 104 , 105 , 106 ] Abbreviations: Aβ, amyloid-β; Apo-E, apolipoprotein-E; BDNF, brain-derived neurotrophic factor; DTG, di-o-tolylguanidine; EGFR, epidermal growth factor receptor; GLP-1R, glucagon-like peptide-1 receptor; Insig/Scap, insulin-induced gene/sterol regulatory element-binding protein cleavage-activating protein; LDLR, low-density lipoprotein receptor; MAP1LC3/UVRAG, microtubule-associated proteins 1A/1B light chain 3/UV radiation resistance associated gene protein; mPRα, membrane progesterone receptor alpha; NPC1, Niemann–Pick protein C1; PAIRBP, plasminogen activator inhibitor 1 mRNA-binding protein; PGRMC1, progesterone receptor membrane component 1; S2R, sigma-2 receptor; TME...…”

“…Other studies, however, demonstrate protective effects of decreased S2R. Either TMEM97 knockout or the S2R-selective modulator DKR-1677 provided neuroprotection against ischemia-induced murine retinal ganglion cell degeneration [ 73 ]. Furthermore, using an illumination-induced degeneration model of AMD in Abca/Rdh8-null mice, S2R-selective modulation using CM398 reduced photoreceptor loss and accumulation of retinal autofluorescent granules, a marker of retinal pigment epithelium cell degeneration [ 84 ].…”