Pathogenesis in Segmental Demyelination

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Project Summary Abstract: Segmental demyelination is a pathologic process of stripping off the myelin sheath, which shunts current out of axons and results in the failure of action potential propagation in a variety of peripheral nerve diseases. However, the molecular program that leads to the demyelination remains unclear, which hampers the therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in FIG4 gene develop Charcot-Marie-Tooth disease type-4J (CMT4J), a disease characterized by segmental demyelination. Our preliminary studies in a CMT4J mouse model (Fig4−/−) have demonstrated that segmental demyelination is associated with increased intracellular Ca2+ in myelinating Schwann cells and macrophages accumulation in the spinal roots. Administering a Ca2+ chelator suppresses the demyelination in Fig4−/− mice. Therefore, this mouse becomes an excellent model to investigate the molecular events underlying demyelination. Toward this end, we will test our central hypothesis that signals from FIG4-deficient axons and/or macrophages exacerbate the overload of intracellular Ca2+ in FIG4-deficient Schwann cells, leading to segmental demyelination. We propose three Specific Aims: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient macrophages release cytokine IL12B that triggers further increases in intracellular Ca2+ in FIG4-deficient Schwann cells, leading to demyelination; (3) Individual proteins in the PAS complex have different roles in the development and maintenance of myelin and axons. These studies will have the potential to uncover novel molecular mechanisms underlying demyelinating peripheral neuropathies and identify targets for therapeutic development.