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Yonju Ha, Eric P. Zorrilla, Preethi Ganapathy, Cory Williams, Vadivel Ganapathy, Sylbia B. Smith; Transient Elevation Of Bip/grp78 Is Associated With Early Preservation Of Sigma Receptor 1 (R1) Null Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5442.
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© ARVO (1962-2015); The Authors (2016-present)
σR1 is a molecular chaperone that binds the ER stress protein BiP/GRP78; ligands for σR1 confer robust neuroprotection in vitro & in vivo. To understand mechanisms by which σR1 mediates retinal neuroprotection, we analyzed σR1 null (-/-) mice. Comprehensive analysis of retinal morphology & function revealed no alterations during the first several weeks in σR1-/- mouse retinas. In the present study, we (1) asked whether alterations in BiP/GRP78 accounted for early retinal preservation; (2) performed morphologic analyses of retinas of σR1-/- mice at older ages; (3) investigated the susceptibility to oxidative stress of ganglion cells (GCs) isolated from σR1-/- mice.
(1) Temporal expression of BiP/GRP78 was analyzed by RT-PCR & WB in σR1-/- retina through 24 wks. (2) Analysis of eyes used TUNEL assay in retinal sections to detect cell death & EM evaluation of optic nerve head (ONH) in mice through 33 wks. (3) GCs were immunopanned from 3 day σR1-/- mice, subjected to oxidative stress (X:XO 10µM:2mU/ml, 18h) in the presence/absence of σR1 ligand ((+)-pentazocine, (+)-PTZ)) & analyzed for cell death.
(1) RT-PCR & WB revealed transient marked increase in BiP/GRP78 expression in σR1-/- mice through ~6wks; expression declined to less than wildtype levels by 18-24 wks. (2) Significantly more TUNEL-positive cells were observed in the ONH of σR1-/- mice by 18 wks; EM revealed disrupted ONH axons containing swollen mitochondria and apoptotic cells in the ONH & GC layer. (3) Primary GCs from neonatal σR1-/- mice were viable & projected neurite processes (axons/dendrites). ~20-22% of σR1-/- GCs died upon 18h X:XO exposure (similar to ~25% in wildtype); they were not protected by (+)-PTZ.
Early normal appearing retinal structure/function of σR1-/- mice is accompanied by transiently increased expression of BiP/GRP78, however with age (25-30 wks), subtle disruption of the retina is detectable of σR1-/- mice characterized by alterations in the ONH & apoptosis of GCs. Absence of σR1 may increase retinal susceptibility to stress concomitant with declining levels of BiP/GRP78.
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