Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, and Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Address for correspondence: Mark P. Mattson, Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, MD 21224. Voice: 410-558-8463; fax: 410-558-8465. mattsonm{at}grc.nia.nih.gov
Ann. N.Y. Acad. Sci. 1012: 37-50 (2004).
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 ß-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.
