The ALS Association (ALSA) is pleased to announce a new project that began April 1, 2003 to establish whether neuronal nitric oxide is involved in disease mechanisms leading to motor neuron death in ALS. Dr. Grigori Enikolopov has generated a mouse that does not express a key enzyme, neuronal nitric oxide synthase (nNOS), required for the synthesis of nitric oxide. This mouse will be bred with three different mutant mice -- those expressing the G93A, G85R and G37R mutation in Cu/Zn superoxide dismutase 1 (SOD1) -- to determine whether in the absence of this enzyme, the life span of mutant SOD1 mice is increased.

Background: Nitric oxide, a common gas, is needed for normal functions in the body and plays a vital role in the brain, carrying messages between cells allowing activities such as memory and learning to take place. However, evidence suggests that excessive or mistimed activation of nitric oxide may lead to cell death mechanisms. The role of nitric oxide in ALS remains controversial, some studies implicating it in disease and others arguing that it does not play a key role.

In an ALSA-funded study, Dr. Christopher Henderson showed that motor neurons isolated from mutant SOD1 mice and grown in a dish, were particularly vulnerable to nNOS-mediated cell death and inhibitors of this enzyme prevented cell death. This study, although promising, needs to be validated in an in vivo system such as the mutant SOD1 mouse model. Earlier studies to test the role of nNOS by a similar breeding strategy failed to show increased survival; however, genetic manipulation of the mouse used for that study failed to completely eliminate the production of NOS.

Once again, the key question that will be answered in this new study is whether neuronal nitric oxide plays a key role in cell death mechanisms in ALS. The outcome of this study has important implications for the design of new therapies to interfere with this pathway.