Abstract
Exposures to high levels of environmental selenium have been associated with motor neuron disease in both animals and humans and high levels of selenite have been identified in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). We have shown previously that exposures to high levels of sodium selenite in the environment of Caenorhabditis elegans adult animals can induce neurodegeneration and cell loss resulting in motor deficits and death and that this is at least partially caused by a reduction in cholinergic signaling across the neuromuscular junction. Here we provide evidence that reduction in insulin/insulin-like (IIS) signaling alters response to high dose levels of environmental selenium which in turn can regulate the IIS pathway. Most specifically we show that nuclear localization and thus activation of the DAF-16/forkhead box transcription factor occurs in response to selenium exposure although this was not observed in motor neurons of the ventral cord. Yet, tissue specific expression and generalized overexpression of DAF-16 can partially rescue the neurodegenerative and behavioral deficits observed with high dose selenium exposures in not only the cholinergic, but also the GABAergic motor neurons. In addition, two modifiers of IIS signaling, PTEN (phosphatase and tensin homolog, deleted on chromosome 10) and PINK1 (PTEN-induced putative kinase 1) are required for the cellular antioxidant reduced glutathione to mitigate the selenium-induced movement deficits. Studies have suggested that environmental exposures can lead to ALS or other neurological diseases and this model of selenium-induced neurodegeneration developed in a genetically tractable organism provides a tool for examining the combined roles of genetics and environment in the neuro-pathologic disease process.