Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is the most common motor neuron disease in humans, affecting one in 1,000. It results in a progressive loss of motor neuron function, leading to paralysis and death, typically within five years of diagnosis. A mutation in the gene for superoxide dismutase SOD1, an enzyme involved in the control of oxidative stress, causes ALS in two percent of human patients, and induces an ALS-like disease in transgenic mice. However, the cause of over 98 percent of ALS cases remains unknown. A report in the June issue of Nature Genetics points to a new suspect: vascular endothelial cell growth factor (VEGF). Expression of this gene is elevated in response to hypoxia, and disrupting the hypoxia response element of the promoter of the VEGF gene results in an age-dependent degeneration of motor neurons in mice. The mice develop the disorder at between five and seven months of age, and have all the hallmarks of ALS, including microaccumulations of neurofilament in neurons of the spinal cord and brain stem, degeneration of motor neurons and muscle atrophy. The study was carried out by by Peter Carmeliet and his colleagues at University of Leuven, Belgium.

The mutant mice had normal baseline levels of VEGF, but exhibited a significant deficit in the ability to induce increased VEGF expression in response to hypoxia. Pate Skene and Don Cleveland suggest in an accompanying News & Views article that two mechanisms may be involved, or may act in concert, to bring about motor neuron degeneration. One mechanism, supported by in vitro studies, is that VEGF acts as a neurotrophic factor. The second is that VEGF aids the survival of motor neurons through its better-known role in regulating the growth and permeability of blood vessels. Skene and Cleveland note that the motor neurons are among the largest and most metabolically demanding cells in the body, and would be highly vulnerable to deficits in blood supply.

The mice obtained by Carmeliet et al. provide an interesting model with which to explore possible interactions between SOD1, VEGF, and other factors in the pathogenesis of motor neuron disorders. And the finding will undoubtedly unleash intense investigation into a role for VEGF in human ALS.—Hakon Heimer

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Primary Papers

  1. . Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet. 2001 Jun;28(2):131-8. PubMed.
  2. . Hypoxia and Lou Gehrig. Nat Genet. 2001 Jun;28(2) PubMed.