Multiple sclerosis is a devastating disease of the central nervous system that affects thousands of US veterans. MS frequently initially presents as temporary tingling or numbness in extremities or blurred vision. However, with time these events result in an accumulation of deficits leading to irreversible motor, sensory and cognitive dysfunction. Presently, there are no cures for MS. Treatment are available but their efficacy is highly variable and loss of motor function appears irreversible. Although classically described as a demyelinating disease, more recent studies have shown that axonal pathology is prevalent in MS and that this axonal pathology may be responsible for the irreversible loss of function associated with the disease. Here, we present strong preliminary data that challenge this view of MS. We show that a specific domain along the axon, known as the axon initial segment is structurally disrupted independent of demyelination indicating that axonal pathology in MS is a primary event and not merely consequential to demyelination. Structural disruption of the axon initial segment is functional devastating to the CNS since it is within the initial segment where i is decided whether an action potential will be generated. If our hypothesis is current, then disease onset does not parallel demyelinating episodes but occurs significantly earlier. Although our findings could revolutionize the view of MS onset, more importantly, we present strong preliminary data that disruption of the axon initial segment is reversible. Presently, we provide morphologic data suggesting reversibility. In this proposal we will test functional reversibility. Together, the studies outlined in this proposal are designed to challenge the current thinking of MS onset and the pathologic mechanisms that mediate the earliest stages of the disease. Moreover, we will further investigate the possibility that dysfunction that results form MS is reversible.

Public Health Relevance

Multiple sclerosis is a devastating disease that inflicts sensory, motor and cognitive deficits on thousands of US veterans. Currently, there is no cure and the available therapies have variable results. MS is classically described as a demyelinating disease; however more recent work has demonstrated that much of the irreversible functional loss associated with this disease results from pathology of the nerve cell. Although nerve cell damage is now being investigated, it is being studies as a consequence of chronic demyelination. In this proposal we provide convincing evidence that the nerve cell may be a primary target of the disease. We also present a plausible hypothesis that identifies the cell type that mediates this pathology and finally we show that this primary nerve cell pathology may be reversible.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology B (NURB)
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VA Veterans Administration Hospital
United States
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Benusa, S D; George, N M; Sword, B A et al. (2017) Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner. J Neuroinflammation 14:116
Otani, Yoshinori; Yermakov, Leonid M; Dupree, Jeffrey L et al. (2017) Chronic peripheral nerve compression disrupts paranodal axoglial junctions. Muscle Nerve 55:544-554