Myelin demyelination

Coman I, Barbin G, Charles P, Zalc B, Lubetzki C (2005) Axonal signals in central nervous system myelination, demyelination and remyelination. J Neurol Sci 233 67-71. 

The classic example of demyelination of the CNS is multiple sclerosis (MS), in which a chronic inflammatory lesion is characterised by a sharply demarcated plaque containing preserved axons denuded of myelin. Demyelination also occurs in infectious diseases such as progressive multifocal leucoencephalopathy and acute disseminated leucoencephalitis, but it is the disseminated focal form of MS that will be addressed in this review article. 

Multiple scelerosis is an autoimmune disease mediated by T and B lymphocytes and macrophages. This is characterized by extensive inflammation and demyelination of the myelin sheath that surrounds the nerve fiber. The death of the nerve fiber results in a variety of symptoms that can lead to impairment of movement, paralysis, and death. 

MS, a chronic demyelinating disease of the CNS, is the most common cause of non-traumatic disability among young adults (Frohman et al. 2006). At the cellular level, MS is mediated by myelin-specific CD4h- T cells that destroy oligodendrocytes... 

Exposures of 10 weeks (5 days/week) to 2,500 mg/kg/day trichloroethylene in com oil by gavage resulted in altered myelin thickness in the rat mental nerve, a branch of the trigeminal nerve (Barret et al. 1991). Effects of similar exposures on the rat trigeminal nerve included decreased fiber diameter and altered fatty acid composition in total lipid extracts, indicative of demyelination (Barret et al. 1992). Stronger effects were seen with the trichloroethylene decomposition product dichloroacetylene. 

O MS symptoms are a function of the position of lesions within the CNS. Because myelin increases the speed of nerve impulse transmission, demyelination slows the speed of transmission. No impulses can be transmitted if the axon is transected. The primary symptoms of MS are caused by this delay or cessation of impulses. Secondary symptoms of MS result from the primary symptoms. 

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. 

Taiep rat (acronym trembling, ataxia, immobility, epilepsy, paralysis) AR Unknown Impaired myelin formation followed by demyelination in the CNS accumulation of microtubules in oligodendrocytes interferes with transport of myelin proteins or mRNAs see text 49... 

Myelin sheaths contain other proteins, some of which have only recently been established as myelin-related. The proteins described above represent most of the well-established myelin proteins that are myelin-specific or have been studied primarily in the context of myelin and demyelinating diseases. However, myelin sheaths contain numerous other proteins in smaller amounts that are also in many other cells and/or have only been identified relatively recently. Some of these are in compact myelin but others are enriched in specialized... 

The more recently identified taiep rat mutant (Table 4-2) has impaired accumulation of CNS myelin for up to 2 months followed by a period of demyelination [49], Adult taiep rats have only 10-25% of the normal amount of CNS myelin. The primary genetic lesion has not yet been identified but the mutant oligodendrocytes exhibit an abnormal accumulation of microtubules during development, suggesting that the mutation may involve a microtubule-associated protein. Biochemical and immu-nocytochemical studies indicate that excessive microtubule accumulation interferes with transport of myelin proteins and/or their mRNAs, eventually leading to a failure of myelin maintenance [49]. 

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. 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

Hattori, N., Yamamoto, M., Yoshihara, T. et al. Study Group for Hereditary Neuropathy in Japan. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32) a clinicopathological study of 205 Japanese patients. Brain 126 134-151,2003. 

Nervous system damage in acquired demyelinating diseases is directed rather selectively against myelin or myelin-forming cells, but axons also are often affected 640... 

MS lesions or plaques can be identified grossly at autopsy (Fig. 38-1) and are sharply demarcated from the surrounding tissue. Plaques occur throughout the white matter, but areas of predilection such as the periventricular white matter are well known. Microscopic examination characteristically shows loss of myelin with preservation of axons (primary demyelination). However, although the most prominent pathology in MS is demye-lination, there are recent indications also for axonal and cortical pathology. Now techniques of confocal microscopy and immunocytochemistry have clearly demonstrated that transected axons are common in MS lesions [9],... 

FIGURE 38-1 Coronal slice of brain from a patient who died with MS. Demyelinated plaques are clearly visible in white matter (large arrows). Small plaques are also observed at the boundaries between gray and white matter (small arrows). (Reproduced with permission from Raine, C. S. The neuropathology of myelin diseases. In P. Morell (ed.) Myelin. New York Plenum Press, 1984, ch. 8.)... 

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