The Formation of Cytoplasmic Rods in Spinal Cord Neurons: A Study of the Effects of Oxidative Stress
Stehman, Christine R.
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A prominent hallmark of amyotrophic lateral sclerosis (ALS) is the presence of proteinaceous cytoplasmic inclusion bodies that contain the cytoskeletal protein actin in neurons. We and others have shown that energy depletion and oxidative stress can induce cytoplasmic rods in cortical and hippocampal neurons. These rods, which contain actin and at least one member of the actin-depolymerizing factor (ADF)/cofilin family of proteins, are thought to be precursors to inclusion bodies. Our goal was to determine if similar conditions would induce the formation of rods in spinal cord neurons. We previously observed the generation of spontaneous rods in spinal cord neurons. To combat this problem, we added antioxidants to growth medium and found that they decreased spontaneous rod formation. In addition, ATP-depletion and peroxide exposure induced rods in spinal cord neurons grown in medium containing antioxidants. The rods induced by ATP-depletion were reversible. In contrast, those induced by peroxide exposure were not. Furthermore, a rapid dephosphorylation (activation) of ADF and cofilin preceded rod formation. Finally, our studies suggest that a minimum level of ADF is critical for rod formation because Swiss 3T3 fibroblasts do not form rods and contain one-third the ADF of cortical neurons and one-ninth the ADF of spinal cord neurons. We propose that oxidative stress and energy depletion promote the formation of ADF /cofilin-actin rods, which may contribute to the neurodegeneration associated with ALS.With honors.