Axon Initial Segment Stability in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by inflammation and demyelination. In addition to these hallmark features, MS also presents with axonal pathology, which is likely responsible for the signs and symptoms of the disease. Although prominent in MS, axonal pathology is frequently considered a consequence of demyelination and not a primary event. This conclusion is consistent with demyelination inducing the loss of specific axonal domains, known as the nodes of Ranvier that are responsible for the propagation of action potentials along the axon. In contrast, we propose that axonal pathology associated with MS is a primary pathological event, independent of demyelination, and not a product of it. In support of our hypothesis, we have analyzed a different axonal domain known as the axon initial segment. Whereas a single axon has numerous nodes of Ranvier uniformly distributed along the axon, each axon contains only a single axon initial segment that is positioned immediately distal to the neuronal cell body. The axon initial segment is responsible for action potential generation and modulation, and hence is essential for normal neuronal function. Background studies conducted by our lab, employing a murine model of demyelination/remyelination, revealed no correlation between axon initial segment stability and myelin integrity. Here we investigate the fate of the axon initial segment in human multiple sclerosis. While not statistically significant, we provide data demonstrating an apparent 40% reduction in AIS numbers in MS. We further provide qualitative evidence that AIS integrity in MS is not dependent on myelination suggestive that axonal pathology may be a primary event in MS, independent of demyelination. Our current findings are intriguing, but unfortunately this study is underpowered, and more samples will be required to determine whether this apparent reduction is statistically significant