New Gene Suspect for ALS

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.

Reference:Oosthuyse B, Moons L, Storkebaum E, Beck H, Nuyens D, Brusselmans K, Van Dorpe J, Hellings P, Gorselink M, Heymans S, Theilmeier G, Dewerchin M, Laudenbach V, Vermylen P, Raat H, Acker T, Vleminckx V, Van Den Bosch L, Cashman N, Fujisawa H, Drost MR, Sciot R, Bruyninckx F, Hicklin DJ, Ince C, Gressens P, Lupu F, Plate KH, Robberecht W, Herbert JM, Collen D, Carmeliet P.
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. Abstract

Skene JP, Cleveland DW. Hypoxia and Lou Gehrig.
Nat Genet. 2001 Jun;28(2):107-8. (News and Views).

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