Exposure to high levels of selenium (Se) has been associated with increased risk of developing the motor neuron disease Amyotrophic Lateral Sclerosis (ALS) in human epidemiologic studies and motor neuron degeneration resembling ALS in livestock animals exposed to high levels of Se under laboratory conditions. Similarly, in C. elegans supplementation of NGM plates with sodium selenite (NaSe) induces a progressive paralysis involving motor neuron degeneration. Assessment of motor neuron morphology in Se-treated animals expressing a pan-neuronal GFP (Punc-119::gfp, Maduro and Pilgrim 1995), demonstrated classical signs of neuronal injury including: neuronal swelling, loss of the nucleus cytoplasm boundary, loss of chromatin staining, axonal blebbing/beading along the ventral cord, and altered mitochondrial morphology. The morphologic changes observed do not phenocopy the changes described in the mec neurodegeneration pathway since it involves much less swelling and is not genetically suppressible by
cad-1(rf),
vha-2(rf), or
crt-1(rf) (Bianchi, et al. 2004). In addition, the Se-induced neurodegenerative changes do not phenocopy hypoxic changes in that pharyngeal and body wall muscles seem to be spared (Scott, et al., 2003). In order to determine what signaling pathways might be involved in this process we have screened the major stress-activated growth factor pathways in C. elegans for effects on Se-induced neurodegeneration. These studies have found that reduced signaling through the TGF-<font face=symbol>b</font> cascade powerfully sensitizes animals to Se-neurotoxicity. In contrast, decreased signaling through the insulin signaling pathway (Tissenbaum and Ruvkun, 1998), in
daf-2(rf) and
age-1(rf), resulted in significant resistance to Se-neurotoxicity. These insulin-pathway effects on Se-neurotoxicity appear to involve alterations in neuroprotective gene expression since reduction-of-function in
daf-16(
m26 and mgDf50), a gene encoding a transcriptional effector of insulin signaling, conferred increased sensitivity to Se exposure. Since the insulin cascade regulates expression of various antioxidant enzymes these results suggested that high environmental Se induces neuronal injury through increasing oxidative stress. Consistent with this hypothesis both glutathione and quercetin significantly reduced the emergence of paralysis under conditions of high environmental Se. Collectively, these results show that Se-neurotoxicity in C. elegans involves features associated with ALS pathology including: motor neuron degeneration, increased oxidative stress, mitochondrial injury, and DNA damage.