Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor

作者：Mavlyutov Timur A; Nickells Robert W; Guo Lian Wang^*

来源：Molecular Vision, 2011, 17(116): 1034-1043.

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 +/- 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 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.

• 出版日期2011-4-26