The interaction between myelin forming cells and axons is one of the best described examples of cell-cell 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. Historically, 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 extend these observations by comparing paranodal axoplasm in myelinated and dysmyelinated axons using time lapse imaging and 3- dimensional electron microscopy.
In month-old dysmyelinated axons, we detect alterations in the distribution of axonal mitochondria and their associations with smooth endoplasmic reticulum.
By 6 months of age, the stability, length and orientation of microtubules which contain increased phospho tau epitopes were detected.
Alterations in microtubules inhibit axonal transport and contribute to paranodal axonal swellings due to organelle accumulation. These data provide compelling evidence that myelin facilitates axonal organelle morphogenesis and distribution. In addition, 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. |
