1st Oct, 2002
Genomics and Genetics Weekly
Oxidative stress is implicated in a fast-growing list of human conditions, from the superficial (e.g., wrinkled skin) to the deadly: diseases such as cancer, heart disease and neurodegenerative disorders including Lou Gehrig disease (amyotrophic lateral sclerosis or ALS).
Researchers at the Jackson Laboratory announced that they have located a gene that protects certain brain and retinal neurons from oxidative stress, and prevents neurodegeneration.
Many normal metabolic functions produce free radicals - highly unstable forms of oxygen. Despite their notoriety, these molecules in fact have several beneficial roles, such as helping white blood cells attack bacteria, viruses and virus-damaged cells. Oxidative stress occurs when the number of free radicals exceeds the normal antioxidant capacity of a cell, leading to cell damage.
The research team, headed by staff scientist Susan Ackerman, PhD, discovered that mice from a strain called harlequin have a mutation in the apoptosis-inducing factor (Aif) gene, causing a severe reduction in AIF production. The AIF protein serves as a scavenger of free radicals in certain brain and retinal neurons. Because harlequin mice have much lower levels of AIF, neurons in these mice undergo oxidative stress. The researchers demonstrated that oxidative stress causes neurons to duplicate their DNA in a process known as re-entering the cell cycle. But the neurons cannot successfully divide. They die in the attempt.
The results of Ackerman's team's work, published in the journal Nature, provided a genetic model of neurodegeneration mediated by oxidative stress. They also demonstrated a direct connection between cell cycle re-entry and oxidative stress in an aging central nervous system.
To date, ALS is the one neurodegenerative disorder known to be caused by oxidative damage to neurons. However, oxidative stress has been identified as a possible cause of several later-onset neurodegenerative diseases, and there are also indications that the diseased neurons of Alzheimer patients have duplicated their DNA prior to dying.
The harlequin mouse provides the first model for studying the role of
oxidative stress on aberrant cell cycle re-entry and subsequent death of
neurons (Klein JA, Longo-Guess CM, Rossman MP, et al., The harlequin mouse
mutation downregulates apoptosis-inducing factor. Nature, 2002;419). This
article was prepared by Genomics and Genetics Weekly editors from staff
and other reports.
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