Ride For Life: New study sheds light on motor neuron cell death

Scientists collaborate in an effort to understand the selective vulnerability of motor neurons in ALS and describe a novel pathway specific to motor neurons that leads to cell death. This study, published today in Neuron* sheds new light on cell death in motor neurons and provides potential targets for therapies that should be tested in disease models of ALS. The study was funded in part by The ALS Association through its Lou Gehrig Challenge: Cure ALS initiative.

"Much remains to be done before we can be sure that our results will have practical consequences for ALS patients," says Dr. Christopher Henderson, author on the current publication and recipient of an ALSA grant award. "In particular, we need to show that our findings are valid in the animal models themselves. Nevertheless, we believe that studying exactly how motor neurons degenerate and die in the SOD mice will continue to provide important leads."

The discovery of mutations linked to the ubiquitously-expressed enzyme Cu/Zn Superoxide Dismutase 1 (SOD1) almost ten years ago has fueled dozens of studies, many supported by ALSA, to determine the toxic properties of these mutations and why motor neurons selectively die. Recent studies have demonstrated that cell death is more widespread than just the motor neurons and is likely to involve astrocytes and microglia. How mutations lead to cell death remains controversial.

"This study elegantly addresses the selective vulnerability of motor neurons and indicates how other cell types may also be involved in the death process. Furthermore, the study demonstrates that the presence of mutations in SOD1 make motor neurons more sensitive to the cell death pathway. This important study opens up new avenues to investigate potential targets for therapeutic intervention," states Dr. Lucie Bruijn, Science Director and Vice President, The ALS Association.

Activation of Fas, a member of the death receptor family, stimulated by its ligand FasL leads to activation of two pathways, a novel pathway described in the current study and a previously described pathway (classical FADD/caspase-8). The investigators demonstrate that the novel death pathway is dependent on the activation of neuronal nitric oxide synthase (nNOS). This pathway, specific to motor neurons in culture and not present in any of the other cell types tested, is likely to act together with the classical FADD/caspase-8 death pathway. To test their hypothesis, the investigators used pharmacological interventions to block various steps of the pathway and showed that they could prevent cell death in cultured motor neurons. Furthermore, the activation of this pathway was exacerbated by the presence of mutations in SOD1. Embryonic motor neurons isolated from control and transgenic mice expressing G93A, G85R or G37R SOD1 grown in culture are not differentially sensitive to excessive glutamate stimulation (known to be toxic to motor neurons) or trophic factor withdrawal. The presence of mutant SOD1, however, increases the sensitivity of motor neurons to activation of this death pathway.

Activated microglia and astrocytes produce nitric oxide (NO), shown in this study to play a key role in this death process and may explain their role in the death of motor neurons. It is of particular interest to test the current hypotheses proposed in this in vitro culture study in animal models to demonstrate a role for this pathway in motor neuron degeneration in vivo. If these pathways are indeed involved, they may provide targets for selective therapeutic intervention.

* Raoul C; Estevez, A.G., Nishimune, H., Cleveland, D.W., deLapeyriere, O., Henderson, C.E., Haase, G., Pettmann, B., 2002. Motor Neuron Death Triggered by a Specific Pathway Downstream of Fas: Potentiation by ALS-linked SOD1 Mutations. Neuron, 35: 1-20.

CONTACT: Lucie Bruijn, PhD, lucie@alsa-national.org, or Nancy Nelson, +1-818-880-9007, ext. 213, both of The ALS Association