Murine Leukodystrophies as Tools to Study Myelinogenesis in Normal and Pathological Conditions

Abstract

Myelinogenesis is controlled by several genes. Therefore, the study of mutations affecting myelination should provide better understanding of the assembly and maintenance of myelin, and in the case of similitude with human diseases, a direct insight into the pathogenesis of these diseases. Murine mutants can be bred readily and sequential analyses allow an examination of the dynamic processes of myelination. In this study, we have selected certain aspects of four leukodystrophies in mice.

The precise mechanisms leading to the important myelin deficit observed in the jimpy mutation, a sex-linked recessive trait, are still not completely elucidated. Our results show in jimpy mice severe astrocytic alterations prior to myelin formation. Therefore, abnormalities of oligodendrocytes and possibly axons could be a secondary phenomenon. Nevertheless, a defect involving neuroglia precursor cells cannot be ruled out. At the present time, Pelizaeus-Merzbacher is a disease in which mainly oligodendrocytes appear to be altered. In consequence, our findings in jimpy mice do not support the present contention that this mutation represents a model for Pelizaeus-Merzbacher disease. We propose that the jimpy mutation could be invaluable to study cell-cell interactions at an early stage of myelinogenesis.

Interest in the myelin deficient (mld) mutant derives from the specific lack of one of the major myelin constituents, myelin basic protein, and the concomitant absence of the major electron dense line during the active phase of myelin deposition in the CNS. Our present knowledge points out a defect of gene regulation involving myelin basic protein synthesis. The absence cf this extrinsic membrane component made it possible to catch a glimpse of its role in the formation and maintenance of the complex structure of the myelin sheath in the CNS.

Quaking mice have been considered to represent an arrest of myelinogenesis. This commonly accepted view has to be reconsidered at the light of recent morphological and biochemical findings. An abnormal processing of the myelinassociated glycoprotein could prevent the normal compaction of myelin until the animals reach adulthood.

Twitcher is characterized by extensive central and peripheral demyelination and the presence of intracellular inclusions in macrophages similar to human globoid cell leukodystrophy. In both human and murine diseases, a deficiency of galactosylceramidase activity was demonstrated. Despite the same underlying genetic defect, there are some important differences between the human and murine globoid cell leukodystrophy indicating that results obtained with animal models should be interpreted with circumspection.

In spite of these reservations, relevant information was obtained on myelin formation and maintenance using these mutants and we are confident that a better knowledge of dysmyelinating diseases can be achieved using these experiments of nature.

Key words

Jimpy mouse - Quaking mouse - Myelin deficient mouse (mid) - Twitcher mouse - Globoid cell leukodystrophy (Krabbe's disease) - Pelizaeus-Merzbacher disease - Myelinogenesis - Astrocytes - Oligodendrocytes - Microglia - Myelin basic protein - Myelin associated glycoprotein - Galactosylceramidase - Glial fibrillary acidic protein