Mitochondria, through their pivotal roles in apoptosis and generation of reactive oxygen species (ROS), are increasingly being implicated in the pathogenesis of neurodegenerative diseases. Researchers in the lab of Nils-Göran Larsson at the Karolinska Institute in Stockholm now have generated mitochondrial late-onset neurodegeneration (MILON) mice, which are characterized by a postnatal disruption of the mitochondrial transcription factor A gene (Tfam). This conditional knockout, occurring only in the neocortex and testes, prevents normal transcription of mitochondrial-encoded genes.

MILON mice were viable and developed normally, but after about two months the level of Tfam in the neocortex declined. In-situ hybridizations showed that mitochondrial RNA levels had also decreased markedly by that age and continued to decline to about 50 percent of normal by six months. A similar decrease occurred in the activity of respiratory chain components encoded by the mitochondrial genome, including cytochrome c oxidase and NADH-dehydrogenase.

Morphologically, the neocortex showed nerve cell loss, axonal degeneration, inflammation, and astrocyte activation, the researchers report in today's Journal of Neuroscience. However, these changes only occurred in mice five months or older, indicating a time lag between respiratory chain deficiency and neurodegeneration.

"This is a very interesting paper that clearly shows that mitochondrial dysfunction can cause late-onset brain degeneration, but the pathology is different from what is seen in Alzheimer's or Parkinson's. In [MILON mice] there is a vacuolar degeneration that may be due to the rapidity and severity of the mitochondrial defect," said Flint Beal, chair of the neurology/neuroscience department at Cornell University Medical College.—Tom Fagan

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Primary Papers

  1. . Late-onset corticohippocampal neurodepletion attributable to catastrophic failure of oxidative phosphorylation in MILON mice. J Neurosci. 2001 Oct 15;21(20):8082-90. PubMed.