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The Journal of Neuroscience, October 15, 2001, 21(20):8082-8090

Late-Onset Corticohippocampal Neurodepletion Attributable to Catastrophic Failure of Oxidative Phosphorylation in MILON Mice

Lene Sörensen¹, Mats Ekstrand¹, José P. Silva¹, Eva Lindqvist², Baoji Xu³, Pierre Rustin⁴, Lars Olson², and Nils-Göran Larsson¹

¹ Departments of Medical Nutrition and Biosciences, Karolinska Institutet, Novum, Huddinge Hospital, S-141 86 Huddinge, Sweden, ² Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, S-171 77 Stockholm, Sweden, ³ Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, California 94143, and ⁴ Unite de Recherches sur les Handicaps Genetiques de l'Enfant, Institut National de la Santé et de la Recherche Médicale U393, Hôpital des Enfants Malades, F-75015 Paris, France

We generated mitochondrial late-onset neurodegeneration (MILON) mice with postnatal disruption of oxidative phosphorylation in forebrain neurons. They develop normally and display no overt behavioral disturbances or histological changes during the first 5 months of life. The MILON mice display reduced 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 respiratory chain deficiency is thus required for the induction of neurodegeneration. Before developing neurological symptoms, MILON mice show increased vulnerability to excitotoxic stress. We observed a markedly enhanced sensitivity to excitotoxic challenge, manifest as an abundance of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactive cells after kainic acid injection, in 4-month-old MILON mice, showing that respiratory chain-deficient neurons are more vulnerable to stress. At ~5-5.5 months of age, MILON mice start to show signs of disease, followed by death shortly thereafter. The debut of overt disease in MILON mice coincides with onset of rapidly progressive neurodegeneration and massive cell death in hippocampus and neocortex. This profound neurodegenerative process is manifested as axonal degeneration, gliosis, and abundant TUNEL-positive nuclei. The MILON mouse model provides a novel and powerful tool for additional studies of the role for respiratory chain deficiency in neurodegeneration and aging.

Key words: mitochondria; respiratory chain; reactive oxygen species; ROS; neurodegeneration; oxidative stress; apoptosis; oxidative phosphorylation; OXPHOS; cre-loxP; Tfam; mitochondrial transcription factor A; MILON; neocortex; hippocampus

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21208082-09$05.00/0

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