Copper plays a key role in brain development, function and survival. Alteration of its homeostasis is suggested to be an aetiological factor in several neurodegenerative diseases. However, the molecular mechanisms relating copper to neurodegeneration are still unknown. In the present report, using morphological analyses of brain sections of mottled/brindled mutant (Mo(br/y)) mice, the animal model of the human genetic copper deficiency associated with neurodegeneration (Menkes' disease), we demonstrated that a high degree of apoptotic cells is present in the neocortex and in the hippocampus. Biochemical characterisation revealed decreased levels of copper content and of the activity of the mitochondrial copper-dependent enzyme cytochrome c oxidase. Copper, zinc-superoxide dismutase activity also shows a slight decrease, while no change was observed for glutathione content. Lower levels of ATP were also found, indicative of a copper-dependent impairment of energy metabolism. Changes appear to be specific for the brain, since no alterations in the activity of liver enzymes were found, although the level of copper was strongly decreased. We also tested biochemical factors involved in cell commitment to apoptosis. The expression of the anti-apoptotic protein Bcl-2, which plays a fundamental role in brain development and morphogenesis, was dramatically decreased and the levels of cytochrome c released from mitochondria into the cytosol were significantly increased. On the basis of these findings, we propose that down-regulation of Bcl-2 can cause neurodegeneration triggered by mitochondrial damage due to copper depletion during brain development in Mo(br/y) mice.
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