A Cell-Specific Death Program Claims Motoneurons

It appears that a particular cell-death pathway can be restricted to one class of neurons, suggesting a mechanism for the specificity of neuronal death in diseases ranging from ALS to Alzheimer’s. In today’s Neuron, Christopher Henderson, Cedric Raoul, and colleagues at INSERM in Marseille, France, the University of Alabama at Birmingham, and the University of California, San Diego, investigate the hypothesis that the selective death of motoneurons in amytrophic lateral sclerosis could depend on the triggering of a Fas-related pathway.

Fas is a so-called “death receptor,” linked to an intracellular caspase cascade ending in cell death. The researchers found a novel pathway linked to the Fas receptor in embryonic mouse motoneurons. Its key step is the transcriptional regulation of neuronal nitric oxide synthase by a cascade involving, in sequence, the Fas-associated protein Daxx; apoptosis signal-regulating kinase 1(ASK1); and p38 kinase. Working in concert with the classic Fas cascade, activation of the novel pathway can trigger cell death. However, there was no evidence for this pathway in other cell types reported to be responsive to Fas (fibroblasts, thymocytes, embryonic cortical neurons).

Henderson et al. then cultured motoneurons from three different transgenic ALS mouse models. These mice carry some of the identified defects in the gene for superoxide dismutase 1 (SOD1), which have been linked to about twenty percent of familial ALS cases. The SOD1 transgenic neurons were highly vulnerable to exogenous Fas agonists and NO. As evidence that this vulnerability was not a function of the in-vitro system, the researchers demonstrated that other SOD1 mouse cells were not any more vulnerable to trophic deprivation or excitotoxic stimulation than were wild-type neurons or other types of control cells from brain or other tissues.
“The model we have illustrated here for the specific case of motoneurons and mouse models of ALS may be more generally applicable: neuronal class-specific pathways for degeneration or death, potentially sensitized by genetic or environmental factors,” the authors write.

This may be highly significant for identifying viable therapies, Zhi-Qi Xiong and Jim McNamara of Duke University in Durham, North Carolina, point out in an accompanying editorial. “Because apoptosis is also critical to diverse physiological processes, nonselective anti-apoptotic agents have practical limitations (Nicholson et al. 2000). The finding of a cell type-specific apoptosis pathway provides new molecular targets by which apoptosis in a specific cell type might be selectively modulated without adverse effects on other systems,” they write. -Hakon Heimer

Reference:Raoul C, Estevez AG, Nishimune H, Cleveland DW, deLapeyriere O, Henderson CE, Haase G, Pettmenn B. Motoneuron death triggered by a specific pathway downstream of Fas: Potentiation by ALS-linked SOD1 mutations. Neuron. 12 Sep 2002;35:1067-83. (Abstract)

Xiong Z-Q, McNamara JO. Fas(t) balls and Lou Gehrig disease: A clue to selective vulnerability of motor neurons. Neuron. 12 Sep 2002;35:1011-4. (Abstract)

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