Amyotrophic Lateral Sclerosis-Associated Persistent Organic Pollutant <i>cis</i>-Chlordane Causes GABA<sub>A</sub>-Independent Toxicity to Motor Neurons, Providing Evidence toward an Environmental Component of Sporadic Amyotrophic Lateral Sclerosis
Daniel Kulick, Emily Moon, R. Madison Riffe, Gregory Teicher, Simon Van Deursen, Aaron H. Berson, He Wu, Gloster B. Aaron, Gerald B. Downes, Stephen H. Devoto, Alison O’Neil
Abstract
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.