Myelin disruption

The functional significance of myelin is revealed by the neurological deficits observed in patients with multiple sclerosis. This disorder is caused by the demyelination of neurons in the brain, spinal cord, and optic nerve. The loss of myelin disrupts the normal conduction of impulses along the axons of these neurons and results in weakness, numbness, loss of bladder control, and visual disturbances. 

In thiamin-deficient rats, electron microscopy of the sciatic and plantar nerves shows distally pronounced axonal degeneration, with an increase in the number of mitochondria and proliferation of vesicular elements of the endoplasmic reticulum. This is followed by disintegration of neurotubules and neurofilaments, and finally axonal shrinkage and myelin disruption (Pawlik etal., 1977). 

The net physiological consequences of immune-mediated myelin disruption are partial or total conduction block, slowing of conduction, and ephaptic cross-activation due to disruption of salutatory conduction mediated by the nodes of... 

Coating of axons by myelin sheets produced by oligodendrocytes (in the CNS) and Schwann cells (in the PNS) provide electrical insulation and make transmissions along the axon more rapid [97]. The peak level of myelin synthesis in vivo takes place in the second week postnatally in rats and during the last trimester in humans [10]. However, the process of myelin formation continues during development into adulthood making the nervous system sensitive to myelination disrupters for an exceptionally long period [98]. 

In diabetic rats, TRPVl is enhanced on myelinated fibres and is hyperphos-phorylated by PKC [127]. In accordance with these findings, anti-TRPVl antiserum was shown to ameliorate pain in a murine model of diabetic neuropathy [128]. In humans, the density of TRPVl-positive nerve fibres is increased in women with chronic breast pain [129] and with vulvodynia [19]. Disruption of TRPV 1 gene causes attenuation of bone cancer pain in mice [130]. Pharmacological blockade of TRPVl by agonists relieved pain in AIDS patients [131]. 

Giese, K. P.,Martini, R., Lemke, G., Soriano, P. and Schachner, M. Mouse P0 gene disruption leads to hypomyelination, abnormal expression of recognition molecules, and degeneration of myelin and axons. Cell 71 565-576,1992. 

The response of the axon to loss of myelin is instructive. In the trembler mutant mouse, the axon undergoes a continuing cycle of partial myelination followed by demyelin-ation. The result is a thin or absent peripheral myelin sheath and a reduction in axonal caliber (Fig. 8-6). Remarkably, this reduction in axonal caliber is highly localized to segments of axon with disrupted myelin. 

Wallerian degeneration is the secondary disruption of the myelin sheath and axon distal to the injury 518... 

Tire anatomy of the brain is quite complex, and only a few terms will be defined here. Tire cerebrum, which is made up of two hemispheres, accounts for the largest part of the brain. Tire deeply folded outermost layer, the cerebral cortex, consists of gray matter, a mass of cell bodies, and fine unmyelinated nerve fibers. Beneath this lies a layer of white matter made up of myelin-covered axons connecting the cerebral cortex with other parts of the brain. Tire two cerebral hemispheres are connected by the corpus callosum, a band of 2 x 108 nerve fibers. Remarkably, these fibers can be completely severed with a relatively minimal disruption of the nervous system. In the past the corpus callosum was sometimes cut to control almost incessant epileptic seizures that could not be prevented by drugs. The "split-brain" patients suffered relatively little disability as long as both eyes functioned normally. Studies of these patients provided some insights into the differing functions of the two hemispheres of the cerebrum.395... 

Other mutations of this gene cause severe neuropathies of infancy (Dejerine-Sottas disease), and still others lead to disability with a late onset (Shy et al., 2004). MPZ mutations disrupt the tertiary structure of PO protein, interfering with PO-mediated adhesion during myelination and with myelin compaction. In contrast, late onset neuropathies result from mutations that allow myelination but chronically disrupt Schwann cell-axonal interactions. A genotype/phenotype correlation is clear even though penetrance can vary within single families. 

Myelin galactolipids are essential for the proper formation of axo-glial interactions. Disruption of these interactions results in profound abnormalities in the... 

Chow E, Mottahedeh J, Prins M, Ridder W, Nusinowitz S, Bronstein JM (2005) Disrupted compacdon of CNS myelin in an OSP/Clau-din-11 and PLP/DM20 double knockout mouse. Mol Cell Neurosci 29 405 13. 

---