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

Abstract

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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  • Authors+Show Affiliations

    ,

    Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy. luisa.rossi@uniroma2.it

    , , , ,

    Source

    Neuroscience 103:1 2001 pg 181-8

    MeSH

    Adenosine Triphosphate
    Animals
    Apoptosis
    Blotting, Western
    Brain
    Copper
    Disease Models, Animal
    Electron Transport Complex IV
    Glutathione
    Hippocampus
    In Situ Nick-End Labeling
    Male
    Menkes Kinky Hair Syndrome
    Mice
    Mice, Mutant Strains
    Neocortex
    Nerve Degeneration
    Proto-Oncogene Proteins c-bcl-2
    Superoxide Dismutase

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    11311799

    Citation

    Rossi, L, et al. "Neurodegeneration in the Animal Model of Menkes' Disease Involves Bcl-2-linked Apoptosis." Neuroscience, vol. 103, no. 1, 2001, pp. 181-8.
    Rossi L, De Martino A, Marchese E, et al. Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis. Neuroscience. 2001;103(1):181-8.
    Rossi, L., De Martino, A., Marchese, E., Piccirilli, S., Rotilio, G., & Ciriolo, M. R. (2001). Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis. Neuroscience, 103(1), pp. 181-8.
    Rossi L, et al. Neurodegeneration in the Animal Model of Menkes' Disease Involves Bcl-2-linked Apoptosis. Neuroscience. 2001;103(1):181-8. PubMed PMID: 11311799.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Neurodegeneration in the animal model of Menkes' disease involves Bcl-2-linked apoptosis. AU - Rossi,L, AU - De Martino,A, AU - Marchese,E, AU - Piccirilli,S, AU - Rotilio,G, AU - Ciriolo,M R, PY - 2001/4/20/pubmed PY - 2001/5/26/medline PY - 2001/4/20/entrez SP - 181 EP - 8 JF - Neuroscience JO - Neuroscience VL - 103 IS - 1 N2 - 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. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/11311799/Neurodegeneration_in_the_animal_model_of_Menkes'_disease_involves_Bcl_2_linked_apoptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306452200005625 DB - PRIME DP - Unbound Medicine ER -