Demyelination and Wallerian Degeneration

One of the characteristic features of peripheral neuropathies with predominantly demyelinating phenotype has been that the degree of clinical severity is associated with the progressive axonal loss rather than the degree of demye-lination. In recent years, as the genes underlying many of the inherited human demyelinating neuropathies have been identified, animal models of these diseases have been developed (Adlkofer et al., 1995; Anzini et al., 1997; Shy et al., 1997; Previtali et al., 2000; Wrabetz et al., 2000). In all of these animal models, the genetic abnormality is in proteins expressed primarily by the myelinating cells, oligodendro-cytes and Schwann cells, and results in disturbances of proper myelination. Although there are minor differences, however, a common theme among all of these genetic disturbances has been the age-related progressive distal axonal loss (Martini et al., 1995; Muller et al., 1997).

This observation raises an important question: Does demyelination, by itself, lead to axonal loss? This important issue has specific relevance to multiple sclerosis. As discussed elsewhere in this book, in recent years, it has been recognized that axonal loss rather than demyelinating plaques are the major determinants of clinical severity in multiple sclerosis; similar to the demyelinating inherited peripheral neuropathies. This is a complex issue to answer. Although the genetic defects in these animal models of peripheral neuropathies are in different proteins, they are all components of myelin. They could easily affect axon-Schwann cell communication in such a way that Schwann cells fail to provide necessary growth factors to the axons, and this process may have nothing to do with demyelination or failed myelination.

One potential mechanism by which demyelination can lead to axonal degeneration is disruption of axonal transport through demyelinated segments (Rao et al., 1981; Guy et al., 1989; Munoz-Martinez et al., 1994; Kirkpatrick et al., 2001). This is more apparent in the optic nerve system where local injections of very small quantities of anti-Gal-C antibody can lead to focal demyelination and abnormal axonal cytoskeleton and axonal transport through the demyelinated segment (Zhu et al., 1999). Similarly, in animal models of experimental allergic neuritis, there are axonal transport deficits in the optic nerve (Rao etal., 1981; Guy et al., 1989). The issue is less clear in the PNS; demyelination in the sciatic nerve induced by focal injection of a neurotoxin from K. humboldtiana causes slowed fast axonal transport (Munoz-Martinez et al., 1994), but demyelination induced by intraneural injection of antigalac-tocerebroside does not have any effect on fast axonal transport (Armstrong et al., 1987).

The issue of axonal degeneration induced by demyelina-tion is further complicated by the presence of inflammatory reaction in almost all of the models of inherited demyelinat-ing peripheral neuropathies. It is possible that inflammation secondary to demyelination may result in axonal loss rather than axonal degeneration resulting from demyelination per se. In recent studies, when Martini and colleagues crossed either the P0-deficient or connexin-32-deficient mice with mice lacking mature B- and T-lymphocytes resulting from absence of recombination activating gene-1

(RAG-1), they found that the double mutants had reduced demyelination and more important, reduced axonal loss (Schmid et al., 2000; Kobsar et al., 2003). Because these animals also had reduced demyelination, it is unclear if the effect of absence of a mature immune system was on demyelination or secondary axonal loss. Further studies are needed to delineate the exact role the immune system plays in demyelination and axonal loss.

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