: Although defects in mitochondrial respiration have been associated with neurodegenerative disorders, the correlation between specific defects and clinical phenotypes remains unclear. The availability of genetic models with defects in different respiratory chain complexes would provide a powerful model system to assess these associations. We propose to create mouse models bearing defects in specific respiratory complex. These mice will be generated by replacing endogenous genes coding for factors that are essential for the assembly of complex I or IV with genes tagged with loxP sequences. Subsequently, loxP tagged animals will be crossed with mice expressing the Cre recombinase in specific tissues, particularly with ones expressing this recombinase in the central nervous system. We will characterize the defects in such animals at the molecular and biochemical level and study their phenotype at different ages. Since the level of gene disruption by the Cre/loxP system can be titrated, we expect to generate lines of transgenic mice that will be partially deficient thereby mimicking neurodegenerative processes.
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