DNA Differences Add Risk: Altered genes show up in Lou Gehrig’s disease

Scientists’ best efforts have failed to vanquish amyotrophic lateral sclerosis (ALS). There was no cure for the nerve-degenerating disease when it struck down baseball star Lou Gehrig 64 years ago, and there is none today. In fact, scientists have yet to pinpoint a cause of the disease except in individuals with certain rare genetic mutations.

In the August Nature Genetics, researchers report on other, more common genetic variations that crop up in ALS patients more often than they do in healthy people. Experiments show that similar genetic variations leave mice vulnerable to the sort of nerve degeneration seen in ALS patients, says Peter Carmeliet of Leuven University in Belgium.

He and his colleagues compared genetic profiles of 750 ALS patients with those of 1,219 healthy people of similar age in Belgium, Sweden, and Great Britain. The people with ALS were nearly twice as likely to have one of two variant forms of a gene for the protein called vascular endothelial growth factor (VEGF).

Scientists suspect that many genetic and environmental factors contribute to ALS. However, until recently, there had been little reason to connect VEGF with the disease. The main job of VEGF is to trigger blood vessel growth. But recent studies have revealed that VEGF also has a role in protecting neurons that are stressed because they have too little oxygen. Indeed, the VEGF gene switches on in response to oxygen deprivation.

The three variants that Carmeliet’s team has linked to ALS show up in the gene’s promoter region, the piece of DNA that activates the rest of the gene.

ALS destroys neurons–in particular, those that control muscle movement. Some evidence suggests that this motor-neuron damage in ALS stems from a lack of oxygen.

Two years ago, Carmeliet’s team reported that mice lacking the oxygen-sensing part of the VEGF gene showed motor-neuron damage. Other researchers have shown that normal VEGF can hold off degeneration of neurons starved of oxygen while growing in a lab culture.

Motor neurons are susceptible to running short of oxygen because they are “very large neurons which have to work hard to transmit signals over very long distances,” Carmeliet says.

To test whether VEGF protects oxygen-deprived neurons, the European team compared two sets of mice. All were susceptible to ALS-type disease, but some had been bred to have a VEGF gene with a promoter defect. After the scientists shut off blood–and therefore oxygen–flowing to part of the spinal cord, those mice harboring the defect showed significantly more paralysis than the others did.

The mouse experiment suggests that the link between VEGF and ALS seen in the European population study has a biological basis, says David A. Greenberg of the Buck Institute for Age Research in Novato, Calif. A shortage of VEGF “is not necessarily causing ALS, but it is somehow increasing the risk for it,” he says.

“This is a beautiful study [that will] spur basic neuroscientists to study VEGF much more than they have in the past,” says Solomon H. Snyder of Johns Hopkins Medical Institutions in Baltimore. “Researchers are going to jump all over this.”


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