Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice

We generated mitochondrial late-onset neurodegeneration (MILON) mice with p ostnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histologi cal changes during the first 5 months of life. The MILON mice display reduc ed levels of mitochondrial DNA and mitochondrial RNA from 2 and 4 months of age, respectively, and severely respiratory chain-deficient neurons from 4 months of age. Surprisingly, these respiratory chain-deficient neurons are viable for at least 1 month without showing signs of neurodegeneration or major induction of defenses against oxidative stress. Prolonged neuronal re spiratory chain deficiency is thus required for the induction of neurodegen eration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensi tivity to excitotoxic challenge, manifest as an abundance of terminal deoxy nucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, sho wing that respiratory chain-deficient neurons are more vulnerable to stress . At similar to5-5.5 months of age, MILON mice start to show signs of disea se, followed by death shortly thereafter. The debut of overt disease in MIL ON mice coincides with onset of rapidly progressive neurodegeneration and m assive cell death in hippocampus and neocortex. This profound neurodegenera tive process is manifested as axonal degeneration, gliosis, and abundant TU NEL-positive nuclei. The MILON mouse model provides a novel and powerful to ol for additional studies of the role for respiratory chain deficiency in n eurodegeneration and aging.