ALS is a progressive, fatal, neurodegenerative disease caused by the degeneration of nerves that control voluntary muscle movement. New evidence generated in mice by John Engelhardt and colleagues at Iowa University, Iowa City, has provided insight into the mechanisms responsible for certain forms of the disease and has identified potential targets for the development of drugs to treat individuals with these forms of ALS.

In some individuals, ALS is caused by a mutation in their SOD1 gene. Mice overexpressing this mutant gene (SOD1G93A mice) develop ALS-like disease. In this study, the authors found that the rate of disease progression could be dramatically slowed and survival markedly improved if SOD1G93A mice lacked expression of either Nox1 or Nox2, although the effects were more dramatic in the absence of Nox2. The Nox1 and Nox2 genes are on the X-chromosome and female mice lacking just one copy of either gene showed delayed disease onset, indicating that even a 50% decrease in expression of these proteins provided some protection. These data have led to the suggestion that developing drugs to inhibit the Nox pathway might be of benefit to individuals with ALS.

jci/

N-cofilin also controls the fate of neural stem cells, which are involved in development of the cortex. In its absence more stem cells stop to self-renew and instead start differentiating. This imbalance depletes the pool of neuronal progenitors so that fewer cells can be made to build a complete and functional cortex. The study provides the first proof that proteins affecting actin filament dynamics are involved in neuronal migration disorders.

This might have implications for humans, too, says Gian Carlo Bellenchi from Witke's lab. Like many other cytoskeletal proteins n-cofilin is conserved between mice and humans and it is likely to play a similar role in the development of the human cortex.

This makes the gene encoding n-cofilin an interesting candidate that might be mutated in neuronal disorders such as lissencephaly and other forms of mental retardation.

The mouse model is a powerful tool to further investigate the roles n-cofilin and the actin cytoskeleton play in stem cell physiology and cell migration. Our studies also identified n-cofilin as a potential target molecule that might allow to interfere with stem cell function in diseases where stem cell division has derailed, concludes Christine Gurniak from Witke's group.

embl/