Membrane lipid peroxidation and oxidative modification of various membrane and associated
proteins (e.g., receptors, ion transporters and channels, and signal transduction and
cytoskeletal proteins) occur in a range of
neurodegenerative disorders. This membrane-associated oxidative stress (MAOS) is promoted by redox-active metals, most notably
iron and
copper. The mechanisms whereby different genetic and environmental factors initiate MAOS in specific
neurological disorders are being elucidated. In
Alzheimer's disease (AD), the
amyloid beta-peptide generates
reactive oxygen species and induces MAOS, resulting in disruption of cellular
calcium homeostasis. In
Parkinson's disease (PD), mitochondrial toxins and perturbed
ubiquitin-dependent proteolysis may impair
ATP production and increase oxyradical production and MAOS. The inheritance of
polyglutamine-expanded huntingtin may promote neuronal degeneration in
Huntington's disease (HD), in part, by increasing MAOS. Increased MAOS occurs in
amyotrophic lateral sclerosis (ALS) as the result of genetic abnormalities (e.g.,
Cu/Zn-superoxide dismutase mutations) or exposure to environmental toxins. Levels of
iron are increased in vulnerable neuronal populations in AD and PD, and dietary and pharmacological manipulations of
iron and
copper modify the course of the disease in mouse models of AD and PD in ways that suggest a role for these metals in disease pathogenesis. An increasing number of pharmacological and dietary interventions are being identified that can suppress MAOS and neuronal damage and improve functional outcome in animal models of AD, PD, HD, and ALS. Novel preventative and therapeutic approaches for
neurodegenerative disorders are emerging from basic research on the molecular and cellular actions of metals and MAOS in neural cells.