Hypothesis of double polarization

Mutations in a large number of genes that encode ubiquitously expressed proteins have been found to selectively or predominantly cause neurological disorders. Speculation has been that impaired intra-axonal transport along the long-extended axons is responsible for this tissue specificity. However this hypothesis may be insufficient in that it does not account for the potential role of the glial cells that interact with axons. Both Schwann cells and oligodendrocytes are also long and polarized cells with extended membranes that concentrically wrap around the axon to form myelin. The resultant myelin is largely compacted, which prevents the transport of many intracellular materials or organelles from one end of the membrane to the other. However patent, non-compacted spaces in the myelin, such as Schmidt-Lanterman incisures or paranodal loops, are also long-extended cytoplasmic channels that extend from the cell body to the distal membranes and may also be subject to transport problems. The nervous system therefore distinguishes itself by having a double long-polarized cellular system. Both neurons and myelinating glia must transport materials long distances, making them vulnerable to a variety of insults; and both must interact with each other. Thus, vulnerability of the nervous system may derive from additive impairments not only in axonal transport, but also in glial transport and neuronal-glial interactions.