Mitochondria transgenic mouse model of Leber’s hereditary optic neuropathy

抄録

Leber’s hereditary optic neuropathy (LHON) with frequency of 15 in 100,000 is considered as one of the most prevalent diseases caused by mtDNA missense mutations. Three most common mutations, ND4 m.G11778A resulting in R340H substitution, ND1 m.G3460A resulting in A52T substitution, and ND6 m.T14484C resulting in M64V substitution cause defects in NADH dehydrogenase of mitochondria oxidative phosphorylation and contribute to 80% of LOHN patients. Since the heteroplasmy nature of mitochondria diseases and thousands of mtDNA copies per cell, it has been challenging to develop animal models for LHON. We introduced the mutant ND4 (m.G11778A) gene driven by a mitochondria-specific promoter into mitochondria of mouse zygotes by decorating capsids of adeno-associated virus (AAV) with mitochondria targeting signal (MTS). Using mCherry reporter linked to mutant ND4, the mutant ND4 expression was only observed after 4-cell stage of embryo development. The mitochondrial ND4 transgenic mice show increased body weight and transgene expression in retina. Consistent with LHON, transgenic mice with apparent retinal transgene expression showed impaired visual activity, which is concomitant with thinning of optic nerve. Furthermore, offsprings derived from the female founders backcrossed with wildtype males inherited the LHON-like phenotypes with varied severity, recapitulating the maternal transmission and heteroplasmy nature of mitochondria diseases. Here, we reported an applicable method to develop the LHON, as well as other mitochondria diseases, mouse model for pharmaceutic development.