Published online 22 April 1999 | Nature | doi:10.1038/news990422-4


Inside Lou Gehrig's disease

Nobody knows precisely what causes the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS) - but a report in the May issue of the journal Nature Neuroscience may have filled in some of the gaps.

In the report, Matthias A. Hediger of the Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts and colleagues have established a link between exposure to oxidative damage - a feature of some cases of ALS - and the ability of the body to mop up a substance called glutamate, which is vital to the smooth running of the nervous system but toxic in quantity.

ALS is a chronic disease whose symptoms include the gradual degeneration of motor neurons - the neurons that control movement. Physicist Stephen Hawking is a well-known ALS sufferer, as was the film actor David Niven, and the baseball player Lou Gehrig, after whom the disease is sometimes named. ALS is relatively rare, with an incidence [in the United States] of about one in every 100,000 people. Most cases are 'sporadic' - that is, patients report no family history of the disease. However, in a small percentage of cases - between about five and 10% - the disease does appear to run in families. Hediger and colleagues are particularly interested in these instances of familial ALS (or FALS), partly because one can trace its genetic roots and get some idea of the fundamental causes of the disease.

In a paper in Nature in 1993, Daniel R. Rosen of the Massachusetts General Hospital and colleagues showed that between 15-25% of patients with FALS had mutations in a gene for an enzyme called SOD-1. Short for 'superoxide dismutase', this enzyme is important in removing dangerous substances called 'free radicals', released by certain chemical reactions involving strong oxidizing agents, such as hydrogen peroxide. However, later work revealed that mice without the gene for SOD-1 did not suffer ALS-like symptoms. Instead, ALS-like symptoms were caused by pathologically mutated forms of SOD-1 that increased oxidative damage, rather than moderating it. Rosen and colleagues found that some FALS patients had mutant forms of SOD-1, linking FALS with oxidative damage. The problem then was why oxidative damage should be expressed in the specific set of symptoms that characterise FALS - in short, why neurons?

This is the question that Hediger and colleagues have been investigating. They have been following up reports that ALS may be connected with a problem in mopping up not just free radicals, but an important chemical called glutamate. Glutamate is a neurotransmitter, responsible for conveying messages across the gaps (or 'synapses') that separate individual neurons. However, chronic exposure to glutamate can kill a neuron, and elaborate systems exist to collect and remove excess glutamate. One of the proteins involved is a so-called 'glutamate transporter', GLT-1. Some research has shown that GLT-1 is less effective in ALS patients than in other people.

Hediger and colleagues wondered if there is any connection between mutant SOD-1 and ineffective GLT1. They found that certain mutant forms of SOD-1 exact specific damage on GLT-1, impairing its ability to collect excess glutamate. The implication is that the excess of glutamate would go on to kill neurons, resulting - eventually - in the symptoms of ALS.

This research suggests possible avenues for ameliorating the disease or slowing its progression. In the researcher's test system - based, it must be said, on laboratory prepartions of the egg cells of the frog Xenopus laevis, and not on real patients - some antooxidant chemicals had the potential to block the activities of mutant SOD-1. Interestingly, though, the most famous of all antioxidants - Vitamin C - had no effect.