The ALS Association Reports That Scientists Describe a Novel Death-Pathway; It May Explain Why Motor Neurons Are Vulnerable in ALS

    CALABASAS HILLS, Calif., Sept. 12 /PRNewswire/ -- 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.
 
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SOURCE The ALS Association

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