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ALS is a progressive neurodegenerative disease that affects neurons that control voluntary muscle movements. Environmental toxins such as pesticides and fungicides have been found to be potential causal factors for ALS as they may lead to the formation of toxic TDP-43 aggregation, a hallmark of the disease. Reactive oxygen species (ROS) lead to the formation of these toxic aggregates causing cell death. This study examined whether four pesticides: TS1, TS3, TS21, and TS31, induce toxic TDP-43 aggregation and whether oxidative stress is involved in response to the pesticides. Two experiments were conducted with primary cortical neurons that were isolated from wildtype mice embryos. Neurons were co-exposed to a sublethal dose exposure of the pesticides and reactive oxygen species inhibitors (cotreatments). Results showed that TS1 and TS3 caused TDP-43 toxic aggregation. Additionally, cotreatments that chelated zinc and copper had various degrees of recovery depending on the drug and cotreatment dosage. TS21 and TS31 did not cause toxic TDP-43 aggregation unless cotreated with ZnCl, which increased the intracellular levels of zinc. Further studies must be done with these toxins to determine how they lead to ALS pathology. Key Words: ALS, TDP-43 aggregation, reactive oxygen species, zinc, pesticides

Amyotrophic Lateral Sclerosis (ALS) is a progressing motor neuron disease that affects neurons responsible for voluntary muscle movements such as walking, talking, and breathing. While therapies are developed to treat ALS symptoms, there is no cure for the disease. Toxic environmental chemicals such as pesticides have been found to increase the likelihood of ALS by causing the toxic aggregation of TDP-43, the hallmark protein of the disease. TDP-43 is typically found in the nucleus of neurons. However, in ALS, it delocalizes to the cytoplasm and forms toxic aggregates. Oxidative stress is another factor known to induce TDP-43 aggregation. This study examines whether two pesticides, TS1 and TS3, cause toxic TDP aggregation. Oxidative stress is also studied to see whether it is involved in response to pesticides. Results of this study show that TS1 and TS3 induce toxic TDP-43 aggregation. It is also observed that oxidative stress may play a role in toxic TDP-43 aggregation formation. Further examination of these pesticides and the effects of oxidative stress can lead to novel druggable targets for ALS therapy.