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R Reddy, T Horvath, CJ Barnstable; Uncoupling Protein UCP2 Regulates Programmed Cell Death in the Ganglion Cell Layer of Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1994.
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Mitochondrial uncoupling protein UCP2 is expressed in a number of mammalian tissues and in selected regions of the normal mammalian brain. It is known that UCP2 uncouples mitochondrial oxidative phosphorylation and also plays a critical role in protecting neurons from an injury or insult. In the retina, UCP2 is expressed primarily in retinal ganglion cells (RGCs) and can be detected soon after these cells are born. Purpose: We have used transgenic mice overexpressing UCP2 and knockout mice lacking UCP2 to study the effects of this protein on ganglion cell behavior and development. To determine whether UCP2 modulates the naturally occurring developmental cell death, we have counted the number of degenerating RGCs during the first six days of postnatal development. Methods: Ganglion cells and degenerating ganglion cells were quantified using both morphological and immunocytochemical techniques. Darkly stained neurons in cresyl violet stained sections represented degenerating RGCs, which were confirmed using TUNEL, and activated Caspase-3 staining in the retinal sections. Results: In counts of cell bodies in the adult ganglion cell layer we found that UCP2 overexpressing mice had 48% more cells and UCP2 knockout mice had 20% fewer cells than controls. This suggests that UCP2 can regulate ganglion cell number in the adult. Degenerating profiles of retinal ganglion cells varied in the overexpressing and wildtype mice during development. There was a decrease in the number of degenerating RGCs from 55% to 15% in transgenic UCP2 mice when compared to normal controls from postnatal day one to six respectively. The present results demonstrate that overexpression of UCP2 gene is effective in preventing the degeneration of ganglion cells attributable to naturally occurring cell death. Conclusion: Our observations suggest a significant role for mitochondrial uncoupling proteins in regulating the neuronal loss during normal development. The remarkable rescue capacity of UCP2 overexpression in the retinal ganglion cells makes it an interesting model for studying natural cell death and responses to injury in the central nervous system.
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