Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative
disease characterized by the death of upper and lower motor neurons.
While causative genes have been identified, 90% of ALS cases are not
inherited and are hypothesized to result from the accumulation of
genetic and environmental risk factors. While no specific causative
environmental toxin has been identified, previous work has indicated
that the presence of the organochlorine pesticide cis-chlordane in the blood is highly correlated with ALS incidence. Never
before tested on the motor system, here, we show that cis-chlordane is especially toxic to motor neurons in vitro- and in vivo-independent
of its known antagonism of the GABAA receptor. We find
that human stem-cell-derived motor neurons are more sensitive to cis-chlordane than other cell types and their action potential
dynamics are altered. Utilizing zebrafish larvae, we show that cis-chlordane induces motor neuron and neuromuscular junction
degeneration and subsequent motor deficits in a touch-evoked escape
response. Together, our work points to cis-chlordane
as a potential sporadic ALS exacerbating environmental pollutant.
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