mitochondria, neurodegeneration, Leigh syndrome, nucleotide mutation, oxidative stress, reactive oxygen species (ROS), viral expression system
Because allotopic expression of WT-ATP6 and treatment of T8993G homoplasmic cells with antioxidants both increase ATP synthesis, I propose combining these two approaches into one that employs the AAV vector developed by Manfredi et al. (2002), modified to contain the nuclear encoded mitochondrial manganese superoxide dismutase gene (MnSOD) and WT-ATP6 (Geromel et al., 2001). MnSOD is a free-radical scavenging enzyme that has increased expression in T8993G cells (Mattiazzi et al., 2004; Geromel et al., 2001). I believe overexpression of MnSOD in combination with allotopically expressed WT-ATP6 will increase ATP synthesis compared to primary T8993G neurons that allotopically express WT-ATP6 only (Geromel et al., 2001; Mattiazzi et al., 2004; Manfredi et al., 2002). Thus, the combined ATP synthesis increasing effects of replenishing WT-ATP6 and reducing oxidative stress may increase respiratory efficiency enough to prevent neuronal atrophy. . . . I hypothesize that overexpression of MnSOD in combination with allotopic WT-ATP6 expression will significantly increase ATP synthesis compared to only allotopic WT-ATP6 expression in mutant neurons.
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