Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration.
Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6β(rd10) (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R(-/-) mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.
Department of Cellular Biology/Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912;
Jing
J
Wang
James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912.
Alan
A
Saul
Department of Cellular Biology/Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912;
Penny
P
Roon
Department of Cellular Biology/Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912; James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, GA 30912; Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912 sbsmith@augusta.edu.
Sylvia B
SB
Smith
D000818:Animals; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism*; D012162:Retinal Degeneration / Q000151:congenital / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C517438:Pde6b protein, mouse
(+)-pentazocine; oxidative stress; photoreceptor; rd10 mouse; retinal neuroprotection