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Abstract #46062 Published in IGR 13-2
Accelerated retinal ganglion cell death in mice deficient in the sigma-1 receptor
Mavlyutov TA; Nickells RW; Guo L-WMolecular Vision 2011; 17: 1034-1044
Purpose: The sigma-1 receptor ((sigma)R1), a ligand-operated chaperone, has been inferred to be neuroprotective in previous studies using (sigma)R1 ligands. The (sigma)R1 specificity of the protective function, however, has yet to be firmly established, due to the existence of non-(sigma)R1 targets of the ligands. Here, we used the (sigma)R1-knockout mouse (Sigmar1(-/-)) to demonstrate unambiguously the role of the (sigma)R1 in protecting the retinal ganglion cells against degeneration after acute damage to the optic nerve. Methods: Retinal (sigma)R binding sites were labeled with radioiodinated (sigma)R ligands and analyzed by autoradiography. Localization of the (sigma)R1 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 (sigma)R1 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(plus or minus)7.9% cells remained in the wild-type ganglion cell layer, but only 68.3(plus or minus)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 (sigma)R1 in alleviating retinal degeneration. This conclusion is consistent with the previous pharmacological studies using (sigma)R1 agonists. Thus, our study supports the idea that the (sigma)R1 is a promising therapeutic target for neurodegenerative retinal diseases, such as glaucoma.
L.-W. Guo. Department of Pharmacology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, United States. Email: ianwangguo@wisc.edu
Classification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)