Accelerated Retinal Ganglion Cell Death in Mice Deficient in the Sigma-1 Receptor

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2011 May 5

PMID 21541278

Citations 44

Authors

Timur A Mavlyutov

Robert W Nickells

Lian-Wang Guo

Affiliations

Soon will be listed here.

Abstract

Purpose: The sigma-1 receptor (σR1), a ligand-operated chaperone, has been inferred to be neuroprotective in previous studies using σR1 ligands. The σR1 specificity of the protective function, however, has yet to be firmly established, due to the existence of non-σR1 targets of the ligands. Here, we used the σR1-knockout mouse (Sigmar1(-/-)) to demonstrate unambiguously the role of the σR1 in protecting the retinal ganglion cells against degeneration after acute damage to the optic nerve.

Methods: Retinal σR binding sites were labeled with radioiodinated σR ligands and analyzed by autoradiography. Localization of the σR1 was performed by indirect immunofluorescence on frozen retinal sections. Retinal ganglion cell death was induced by acute optic nerve crush in wild-type and Sigmar1(-/-) mice. Surviving cells in the ganglion cell layer were counted on Nissl-stained retinal whole mounts 7 days after the crush surgery.

Results: Photoaffinity labeling indicated the presence of the σR1 in the retina, in concentrations equivalent to those in liver tissue. Immunolabeling detected this receptor in cells of both the ganglion cell layer and the photoreceptor cell layer in wild-type retinas. Quantification of cells remaining after optic nerve crush showed that 86.8±7.9% cells remained in the wild-type ganglion cell layer, but only 68.3±3.4% survived in the Sigmar1(-/-), demonstrating a significant difference between the wild-type and the Sigmar1(-/-) in crush-induced ganglion cell loss.

Conclusions: Our data indicated faster retinal ganglion cell death in Sigmar1(-/-) than in wild-type mice under the stresses caused by optic nerve crush, providing direct evidence for a role of the σR1 in alleviating retinal degeneration. This conclusion is consistent with the previous pharmacological studies using σR1 agonists. Thus, our study supports the idea that the σR1 is a promising therapeutic target for neurodegenerative retinal diseases, such as glaucoma.

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References

Senda T, Matsuno K, Mita S . The presence of sigma receptor subtypes in bovine retinal membranes. Exp Eye Res. 1997; 64(5):857-60. DOI: 10.1006/exer.1996.0272. View

McKinnon S, Schlamp C, Nickells R . Mouse models of retinal ganglion cell death and glaucoma. Exp Eye Res. 2008; 88(4):816-24. PMC: 3056071. DOI: 10.1016/j.exer.2008.12.002. View

Ramachandran S, Lu H, Prabhu U, Ruoho A . Purification and characterization of the guinea pig sigma-1 receptor functionally expressed in Escherichia coli. Protein Expr Purif. 2006; 51(2):283-92. PMC: 2953794. DOI: 10.1016/j.pep.2006.07.019. View

Langa F, Codony X, Tovar V, Lavado A, Gimenez E, Cozar P . Generation and phenotypic analysis of sigma receptor type I (sigma 1) knockout mice. Eur J Neurosci. 2003; 18(8):2188-96. DOI: 10.1046/j.1460-9568.2003.02950.x. View

Gebreselassie D, Bowen W . Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes. Eur J Pharmacol. 2004; 493(1-3):19-28. DOI: 10.1016/j.ejphar.2004.04.005. View

Tchedre K, Huang R, Dibas A, Krishnamoorthy R, Dillon G, Yorio T . Sigma-1 receptor regulation of voltage-gated calcium channels involves a direct interaction. Invest Ophthalmol Vis Sci. 2008; 49(11):4993-5002. DOI: 10.1167/iovs.08-1867. View

Nickells R . Variations in the rheostat model of apoptosis: what studies of retinal ganglion cell death tell us about the functions of the Bcl2 family proteins. Exp Eye Res. 2010; 91(1):2-8. PMC: 2885977. DOI: 10.1016/j.exer.2010.03.004. View

Ferreira P . Characterization of RanBP2-associated molecular components in neuroretina. Methods Enzymol. 2000; 315:455-68. DOI: 10.1016/s0076-6879(00)15861-6. View

Yao H, Yang Y, Kim K, Bethel-Brown C, Gong N, Funa K . Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: implication for increased monocyte transmigration. Blood. 2010; 115(23):4951-62. PMC: 2890169. DOI: 10.1182/blood-2010-01-266221. View

10.

Keiser M, Setola V, Irwin J, Laggner C, Abbas A, Hufeisen S . Predicting new molecular targets for known drugs. Nature. 2009; 462(7270):175-81. PMC: 2784146. DOI: 10.1038/nature08506. View

11.

Mavlyutov T, Cai Y, Ferreira P . Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization. Traffic. 2002; 3(9):630-40. DOI: 10.1034/j.1600-0854.2002.30905.x. View

12.

Libby R, Li Y, Savinova O, Barter J, Smith R, Nickells R . Susceptibility to neurodegeneration in a glaucoma is modified by Bax gene dosage. PLoS Genet. 2005; 1(1):17-26. PMC: 1183523. DOI: 10.1371/journal.pgen.0010004. View

13.

Tezel G . Oxidative stress in glaucomatous neurodegeneration: mechanisms and consequences. Prog Retin Eye Res. 2006; 25(5):490-513. PMC: 1820838. DOI: 10.1016/j.preteyeres.2006.07.003. View

14.

Mavlyutov T, Ruoho A . Ligand-dependent localization and intracellular stability of sigma-1 receptors in CHO-K1 cells. J Mol Signal. 2007; 2:8. PMC: 2045653. DOI: 10.1186/1750-2187-2-8. View

15.

Kahoun J, Ruoho A . (125I)iodoazidococaine, a photoaffinity label for the haloperidol-sensitive sigma receptor. Proc Natl Acad Sci U S A. 1992; 89(4):1393-7. PMC: 48457. DOI: 10.1073/pnas.89.4.1393. View

16.

Bucolo C, Drago F . Effects of neurosteroids on ischemia-reperfusion injury in the rat retina: role of sigma1 recognition sites. Eur J Pharmacol. 2004; 498(1-3):111-4. DOI: 10.1016/j.ejphar.2004.06.067. View

17.

Su T, Hayashi T, Maurice T, Buch S, Ruoho A . The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci. 2010; 31(12):557-66. PMC: 2993063. DOI: 10.1016/j.tips.2010.08.007. View

18.

Hayashi T, Su T . Sigma-1 receptors (sigma(1) binding sites) form raft-like microdomains and target lipid droplets on the endoplasmic reticulum: roles in endoplasmic reticulum lipid compartmentalization and export. J Pharmacol Exp Ther. 2003; 306(2):718-25. DOI: 10.1124/jpet.103.051284. View

19.

Meunier J, Hayashi T . Sigma-1 receptors regulate Bcl-2 expression by reactive oxygen species-dependent transcriptional regulation of nuclear factor kappaB. J Pharmacol Exp Ther. 2009; 332(2):388-97. PMC: 2812109. DOI: 10.1124/jpet.109.160960. View

20.

Li Y, Semaan S, Schlamp C, Nickells R . Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice. BMC Neurosci. 2007; 8:19. PMC: 1831479. DOI: 10.1186/1471-2202-8-19. View