Overview: Finally, work
with Drs. Zoltan Tökés, Giselle Lim, and Jon Backstrom has
described a class of enzymes, metalloproteinases, that are inactive
in neurodegenerative diseases and may play a role in the pathogenesis of
conditions such as Alzheimer's disease and amyotrophic lateral sclerosis.
The research focus in the laboratory has been on the associations that
initiate, direct, and maintain the unique and highly specialized cells in the
nervous system. Early work
studied the role synaptic input plays in the formation and maintenance of
specialized neurons and local regions on the neuronal surface. Later
work focused on the role neurons play in the formation and maintenance of
the specialized cells that differentiate large amounts of a specialized
membrane, the myelin sheath. From that work has developed a series
of studies on the cell-cell and cell-matrix interactions that influence
the determination of the myelin-forming Schwann cells from neural crest
cells, a population of
cells with many potential cell fates.
Myelin Formation and Maintenance:
Oligodendrocytes of the central nervous system (CNS) and Schwann cells of the the peripheral nervous system (PNS) synthesize and maintain a unique differentiative product, myelin. The myelin membrane sheath enwraps the axon of the neuron and facilitates the conduction of nerve impulses. Normally this sheath forms in response to direct associations between neurons and glial cells, and the membrane is assembled around only one portion of the neuron, the axon. A number of studies have explored: 1) the type of neuronal signal that controls the expression of the myelin phenotype and 2) the components of the myelin membrane that produce and maintain the specialized wrapping and compaction of the sheath.
Return to TOP MAINSchwann Cell Differentiation and Maintenance:
Neural crest cells are a pleuripotent population of cells that gives rise to a variety of differentiated cell types. Lineage decisions and the potential fates of neural crest are influenced by extrinsic factors encountered during migration and subsequent colonization of their final organ sites. Our research concentrates on the developmental conditions that control the expression of the Schwann cell lineage of neural crest cell derivatives. Schwann cells normally develop in association with the axonal process of neurons and depend upon this cell-cell interaction for initiation of synthesis and assembly of the myelin sheath and for maintenance of the mature phenotype. The overall goal is to utilize in vitro and in vivo methods to investigate the developmental plasticity and control mechanisms of Schwann cell differentiation. Elucidation of these mechanisms provides: 1) a better understanding of normal nervous system development and 2) a potential means of producing cells that may be transdifferentiated for neural transplantation following neurodegenerative diseases or injury.
The Role of Metalloproteinases in Neurodegeneration:
Matrix metalloproteinases (MMPs) are a family of enzymes involved with the maintenance and turnover of the extracellular matrix (ECM). MMPs are secreted in a proenzyme form and are activated when their propeptide domain is cleaved. Possible physiological activators include plasmin, kallikrein, superoxide radicals, and serine proteinases. In addition to being secreted in a latent form, MMPs are also secreted in a complex with regulator molecules, the tissue inhibitors of metalloproteinase (TIMPs). Our previous work indicates that specific neurodegenerative conditions are associated with abnormally high expression of brain-derived MMPs in a latent form. The intracellular accumulation of specific inactive proteinases within neurons confined to the degenerative fields of Alzheimer's patients may explain the accumulation of neuritic plaques and the eventual death of these neurons.