研究领域

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Intermediate filaments (IFs) are major components of the neuronal cytoskeleton, reflecting their important role in determining neuronal cytoarchitecture. Up to five different cytoplasmic IF proteins can be expressed in adult neurons and we study four of these, namely, peripherin and the neurofilament (NF) triplet proteins, NFL, NFM and NFH. Overexpression of either of these neuronal IF proteins in transgenic mice can have an adverse effect on defined populations of neurons, such as motor neurons, giving rise to a neurodegenerative disease resembling amyotrophic lateral sclerosis (ALS). The neurotoxicity of these overexpressed IF proteins appears to at least partly be due to their propensity to form aggregates. We are attempting to elucidate pathogenic mechanisms underlying these ALS-like diseases by studying pertinent signal transduction pathways in transgenic mice or in primary neuronal cultures derived from dorsal root ganglia (DRG) of mouse embryos. The primary DRG cultures contain two major cell types: sensory neurons and Schwann cells, which are the glial cells that form myelin in the peripheral nervous system. In addition to neuronal studies involving IFs, we use these cultures to study myelination, which can be induced by adding ascorbate to the culture medium. We are particularly interested in the signal transduction pathways that are activated in myelinating Schwann cells and have recently implicated p38, a member of the mitogen activated protein kinase (MAPK) family, which appears to exert its effect at the level of the actin cytoskeleton. The Schwann cells in DRG cultures can be selectively removed using antimitotic agents and the remaining sensory neurons can be seeded with oligodendrocytes in order to study myelination by glial cells derived from the central nervous system.