Dysmyelination, demyelination and reactive astrogliosis in the optic nerve of the taiep rat.

Taiep is an autosomal recessive mutant rat that shows a highly hypomyelinated central nervous system (CNS). Oligodendrocytes accumulate microtubules (MTs) in association with endoplasmic reticulum (ER) membranes forming MT-ER complexes. The microtubular defect in oligodendrocytes, the abnormal formation of CNS myelin and the astrocytic reaction were characterized by immunocytochemical and ultrastructural methods during the first year of life. Optic nerves of both control and taiep rats were processed by the immunoperoxidase method using antibodies against tubulin, myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP). Taiep oligodendrocytes are strongly immunoreactive against tubulin, indicative of a significant accumulation of microtubules. Early differentiated oligodendrocytes observed with electron microscopy show that MT-ER complexes are mainly present in the cell body. This defect increases during the first year of life; oligodendrocytes show large MT-ER complexes projected within oligodendrocyte processes. Using anti-MBP, there was a progressive reduction of immunolabeling in the myelin sheaths as taiep rats grew older. Ultrastructural analysis revealed severely dysmyelinated axons with a frequently collapsed periaxonal collar. However, through age the myelin sheath became gradually infiltrated by MTs, suggesting their contribution to premature loss of myelin in the taiep rat. Axons of one-year-old taiep rats were severely demyelinated. Modifications in astrocytes revealed by the GFAP antibody showed a strong hypertrophy with increased immunostaining in their processes. As demyelination of axons progressed, taiep rats developed a strong astrogliosis. The present findings suggest that in taiep rats the early abnormal myelination of axons affects the adequate maintenance of myelin, leading to a progressive loss of myelin components and severe astrogliosis, features that should be considered in the pathogenesis of dysmyelinating diseases.

Binding of microtubules to transitional elements in oligodendrocytes of the myelin mutant taiep rat.

The presence of microtubules physically bound to smooth endoplasmic reticulum profiles of oligodendrocytes constitutes the most conspicuous feature observed in the myelin mutant taiep rat. The endoplasmic reticulum membranes associated with microtubules were morphologically characterized as transitional elements that constitute the intermediate compartment according to their topographic location close to the cis-Golgi apparatus. The development of this surprising microtubular defect appears to be associated with the early events of myelination. Transitional elements associated with microtubules operate in protein transport from endoplasmic reticulum to cis-Golgi. This microtubular defect could explain the dysmyelination and neurologic alterations observed in taiep rats. Moreover, these findings allow us to propose that there is a blockage of protein traffic at the intermediate compartment of taiep oligodendrocytes, a situation that could explain the hypomyelinated axons observed in this myelin mutant. The binding of microtubules to membranous organelles promotes the stabilization of microtubules, a feature that has important implications regarding its accumulation within the cytoplasm of oligodendrocytes during the temporal evolution of this neurologic disorder. The taiep rat is a myelin mutant with a long survival and could be a useful model for understanding dysmyelinating diseases in which the intracellular transport of myelin components is affected.