Cellular and Molecular Mechanisms of Cortical Remyelination in MS Patients

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

The purpose of this project is to characterize cortical remyelination in postmortem multiple sclerosis (MS) brains. In contrast to white matter lesions, our preliminary studies establish that new oligodendrocyte production and active remyelination are prominent features of many chronic cortical MS lesions. Two major patterns of cortical demyelination have been described: leukocortical lesions (Type I) and subpial bands of demyelination which can extend over several gyri (Type III). Two specific aims will compare and contrast successful and failed remyelination in chronic Type I and III cortical lesions. Aim I will determine if remyelination is more prevalent in Type I or III lesions, and if there is a difference in repair of grey and white matter regions of Type I lesions. Remyelination requires the production of new oligodendrocytes. The second goal of Aim 1 is to quantify and characterize pre-myelinating and remyelinating oligodendrocytes in type I and III cortical lesions. We will determine the relationship between oligodendrocyte processes and remyelinating internodes and establish whether functional nodes of Ranvier are formed during cortical remyelination. Specific Aim 2 will perform a similar characterization of oligodendrocyte progenitor cell (OPC) density and phenotype in cortical lesions. OPCs are the only source of new oligodendrocytes, and their density and phenotype can regulate the success of myelin repair. Preliminary studies indicate that OPC densities are not altered in cortical lesions. Studies will investigate whether OPC molecular phenotype, OPC and pre-myelinating oligodendrocyte programmed cell death, or OPC mitosis varies in cortical lesions. We will also investigate whether inhibitors of oligodendrogenesis or myelination modulate myelin repair in MS brains. While anti-inflammatory therapies delay the progression of MS, they do not stop the disease process. The future of MS therapeutics lies in the identification of additional therapeutic targets and combinatorial therapies. By characterizing successful and failed myelin repair in MS brains, the studies confined in this proposal should identify novel targets that will enhance repair of the MS brain and quality of life of MS patients.