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GlialAxon Interactions in Health and Disease
Bruce D. TrappDepartment of Neurosciences, Lerner Research Institute, Cleveland Clinic, USA
The interaction between myelin forming cells and axons is one of the best described examples of cellcell
interactions in mammals. Myelin plays multiple roles essential for normal nervous system function. Best
known is the insulation of axons to permit rapid propagation of nerve impulses by saltatory conduction. By
concentrating voltage gated sodium channels at nodal axoplasm myelin also saves energy. To attain similar
conduction speeds of myelinated axons, unmyelinated axons would have to have diameters 100 times larger
than myelinated axons. Myelin, therefore, also conserves space. One of the most clinically relevant functions
of myelin is provide trophic support essential for axonal survival. This function reflects the fact that axons
can be meters away from the neuronal cell body and has to rely on glia support rather than on neuronal gene
transcription to respond to many local changes in environment. Since axonal degeneration is the major cause
of neurological disability in primary diseases of myelin, we have been investigating the mechanisms by which
myelin provides trophic support to axons. The purpose of this presentation is to summarize these studies with
an emphasis on morphological studies of normal and abnormal myelin-axon interactions. Myelin is essential
for long-time axonal survival. This is best illustrated by the primary axonal degeneration that develops in
mice null for the myelin proteins MAG, PLP or CNP. The precise mechanisms by which myelin stabilizes the
axon is poorly understood. Two general features are common to the axonal pathologies that precede axonal
degeneration: the axonal cytoskeleton is abnormal and the pathologies dominate in paranodal regions. We
have compared paranodal axoplasm in myelinated, demyelinated and dysmyelinated axons using time lapse
imaging and 3-dimensional electron microscopy. We detect alterations in transport and distribution of axonal
mitochondria and smooth endoplasmic reticulum following demyelination and dysmyelination. These data
suggest that altered ATP production and calcium homeostasis precede axonal degeneration. In addition the
stability, length and orientation of microtubules which contain increased phospho tau epitopes were detected.
Alterations in microtubules inhibit axonal transport and result in paranodal axonal swellings due to organelle
accumulation. We are also investigating molecular mechanisms responsible for mitochondria fission and fusion
in normal, demyelinated and dysmyelinated axons. These studies are unraveling the cascade of molecular and
morphological changes that eventually result in axonal degeneration so we can identify therapeutic targets that
may delay or stop axonal degeneration in primary diseases of myelin.