Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the dysfunction and death of motor neurons in the spinal cord, brain stem, and motor cortex. Approximately 10% of all ALS cases are familial (fALS) and have been linked to a variety of genetic mutations. About 20% of fALS cases are linked to a mutation in the superoxide dismutase 1 (SOD1) gene. Wild type SOD1 is an antioxidant protein responsible for capturing superoxide radicals and preventing oxidative damage. In individuals with SOD1-linked fALS, SOD1 mutations confer a toxic gain of function, resulting in abnormal protein aggregation that ultimately leads to selective motor neuron dysfunction and death. Research in both mouse and human pluripotent stem cell models of fALS have shown that motor neurons with SOD1 mutations have different electrical properties and firing patterns compared to wild type controls. Some findings suggest that motor neurons with SOD1 mutations are hyperexcitable while others suggest that cells are hypoexcitable. This apparent contradiction has led to the hypothesis that hyperexcitability may be an early, presymptomatic neuroprotective mechanism and that motor neurons transition into a phase of late hypoexcitability following disease onset and progression. The reasons for these changes in excitability are not fully understood, but work in both mice and humans has shown alterations in ion channel expression and permeability as possible causes. Previous work in our labs has shown that motor neurons derived from human embryonic stem cells treated with SOD1 aggregates have a significantly depolarized resting membrane potential and action potential threshold compared to healthy controls, potentially linking SOD1 aggregates to electrophysiological changes. Here, I review the major theories of neurodegeneration and of electrophysiological changes to understand how observed changes in SOD1-linked ALS may ultimately lead to motor neuron death.
EM-Summer-Research-20-Poster-Emily-Moon
Interesting findings!