Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis

Copper plays a key role in brain development, function and survival. Altera tion of its homeostasis is suggested to be an aetiological factor in severa l neurodegenerative diseases. However, the molecular mechanisms relating co pper to neurodegeneration are still unknown. In the present report, using m orphological 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 degre e of apoptotic cells is present in the neocortex and in the hippocampus. Bi ochemical characterisation revealed decreased levels of copper content acid of the activity of the mitochondrial copper-dependent enzyme cytochrome c oxidase. Copper, zinc-superoxide dismutase activity also shows a slight dec rease, while no change was observed for glutathione content. Lower levels o f ATP were also found, indicative of a copper-dependent impairment of energ y metabolism. Changes appear to be specific for the brain, since no alterat ions in the activity of liver enzymes were found. although the level of cop per 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 morphogenesi s, 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 ca n cause neurodegeneration triggered by mitochondrial damage due to copper d epletion during brain development in Mo-br/y mice. (C) 2001 IBRO. published by Elsevier Science Ltd. All rights reserved.