Modeling the Impact of Mitochondrial DNA Damage in Forebrain Neurons and Beyond

We have generated an inducible transgenic mouse model, which expresses a mutated version of UNG1 (mutUNG1) that removes thymine, in addition to uracil from mitochondrial DNA. The abasic-sites (AP-sites) generated by removal of thymine or uracil are a threat to genomic integrity, and are particularly harmful in mitochondria due to inhibition of mitochondrial DNA polymerase. MutUNG1, accompanied by a luciferase reporter-gene, is controlled by the Tet-on system. Transgene expression is spatially regulated by the forebrain specific CaMKIIα-promoter, and temporally by the addition of doxycycline. Mice harboring this transgene develop compromised mitochondrial dynamics, neurodegeneration and impaired behavior.