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Author Contact: emoon@wesleyan.edu
Local Identifier: 1001.pdf
PID: ir:3276"},{"label":"Author-supplied Keywords","value":["Motor neuron","Stem cells","Neurodegeneration","Motor neuron disease","ALS","Electrophysiology"]},{"label":"Degree","value":["Master of Arts"]},{"label":"Description","value":"

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the death of motor neurons in the spinal cord, brainstem, and motor cortex. As a result, patients experience progressive paralysis and the majority die within 3-5 years of diagnosis following respiratory failure. ALS is broadly divided into two categories: familial ALS (fALS), which comprises approximately 10% of all cases, and sporadic ALS (sALS). Very little is known about the mechanisms of motor neuron death in ALS, so gaining a greater understanding of degeneration is vital to developing effective therapeutics. Here we used human embryonic stem cell-derived motor neurons to model ALS and study how disease alters the electrophysiological properties of mature motor neurons. Familial ALS, as the name suggests, is ALS that can be linked to a heritable genetic mutation. Approximately 20% of all fALS cases are linked to mutations in the SOD1 protein, an important antioxidant protein found all throughout the body. SOD1 mutations confer a toxic gain of function, resulting in abnormal protein aggregation. Interestingly, SOD1 aggregates are specifically toxic to motor neurons. Additionally, motor neurons with SOD1 mutations show electrophysiological differences compared to controls. In the present research, we modeled SOD1-linked ALS by treating mature motor neurons with toxic H46R SOD1 aggregates. We found that SOD1 aggregates significantly altered the electrophysiological properties of motor neurons. Treated motor neurons had a reduced ability to fire repetitive action potentials, were depolarized at rest, and had a depolarized action potential threshold. Cases of ALS that are not linked to a heritable genetic mutation are classified as sporadic. Sporadic ALS is thought to be the result of environmental factors such as pesticides, heavy metals, or neurotoxins acting on an individual’s genetic makeup to cause progressive motor neuron degeneration. sALS is difficult to model due to its heterogenic etiology and therefore the mechanisms of motor neuron degeneration are poorly understood. Here, we modeled sALS by applying cis-chlordane, an organochlorine pesticide correlated with an ALS test group, to cultures of mature motor neurons. We found that cis-chlordane treatment altered single and repetitive action potential properties and depolarized resting membrane potential. These findings suggest that the electrophysiological changes motor neurons undergo are different depending on the compound applied to cause disease. Nevertheless, our results help illuminate different neurodegenerative pathways that may be activated in ALS progression.

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