successful amelioration of mitochondrial optic neuropathy using the yeast ndi1 gene in a rat animal model使用酵母ndi1成功改善线粒体视神经病变的基因在大鼠动物模型.pdf

Successful Amelioration of Mitochondrial Optic Neuropathy Using the Yeast NDI1 Gene in a Rat Animal Model 1 1 2 1 1 Mathieu Marella , Byoung Boo Seo , Biju B. Thomas , Akemi Matsuno-Yagi , Takao Yagi * 1 Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America, 2 Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America Abstract Background: Leber’s hereditary optic neuropathy (LHON) is a maternally inherited disorder with point mutations in mitochondrial DNA which result in loss of vision in young adults. The majority of mutations reported to date are within the genes encoding the subunits of the mitochondrial NADH-quinone oxidoreductase, complex I. Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies. Methodology/Principal Findings: We established a rat model which involves injection of rotenone-loaded microspheres into the optic layer of the rat superior colliculus. The animals exhibited the most common features of LHON. Visual loss was observed within 2 weeks of rotenone administration with no apparent effect on retinal ganglion cells. Death of retinal ganglion cells occurred at a later stage. Using our rat model, we investigated the effect of the yeast alternative NADH dehydrogenase, Ndi1. We were able to achieve efficient expression of the Ndi1 protein in the mitochondria of all regions of retinal ganglion cells and axons by delivering the NDI1 gene into the optical layer of the superior colliculus. R