Suppression of complex I gene expression induces optic neuropathy

Optic nerve degeneration is a feature common to diseases with mutations in genes that encode complex I of the respiratory chain. Vulnerability of this central nervous system tract is a mystery, because of the paucity of animal models used to investigate effects of the mutated DNA in tissues rather than isolated in cultured cells. Using a ribozyme designed to degrade the mRNA encoding a critical nuclear-encoded subunit gene of complex I (NDUFA1), we tested whether oxidative phosphorylation deficiency can recapitulate the optic neuropathy of mitochondrial disease. Injection of adeno-associated virus expressing this ribozyme led to axonal destruction and demyelination, the hallmarks of Leber hereditary optic neuropathy.