Investigation of dysmyelinogenesis in caprine beta-mannosidosis: Biochemical, cell culture, morphological, and endocrine studies.

摘要

Central nervous system (CNS) myelin deficiency is a consistent pathological feature of caprine {dollar}beta{dollar}-mannosidosis, an autosomal recessive neurovisceral lysosomal storage disease. The four projects presented in this dissertation were designed to examine some of the factors which could contribute to the myelin deficiency found in affected animals.; Quantification of regional central nervous system oligosaccharide accumulation addressed the possibility of an association between the storage of oligosaccharides and myelin deficits. Results indicate that the extent of regional CNS accumulation of oligosaccharide is not associated with regional differences in severity of myelin deficiency in caprine {dollar}beta{dollar}-mannosidosis.; Cell culture studies examined oligodendrocytes from affected and control animals to compare their number, morphology, and immunostaining characteristics and assess the possibility of intrinsic oligodendrocyte defects. Results indicate that differentiated oligodendrocytes from affected animals do not show morphological abnormalities in culture. However, increased numbers of galactocerebroside-negative bipolar cells, which may be glial progenitor cells, were present in affected animal cultures, suggesting the possibility of a defect in differentiation to mature oligodendrocytes, with persistence of the undifferentiated glia during late stages of development.; Astrocyte changes at various stages of myelination of the optic nerve were examined by in vivo immunocytochemical studies to assess developmental features of astrocytic abnormalities. Results suggest that astrocyte changes are present in the affected animal optic nerve even during early stages of myelination and that changes are not progressive. The increased density of astrocyte processes appears to be due to a greater number of processes extending from astrocytes, although the possibility of an increased number of astrocytes with redistribution of glial fibrillary acidic protein from cell bodies into processes has not been ruled out.; Examination of thyroid morphology and function revealed that extensive and developmentally progressive morphological abnormalities as well as statistically significant thyroid function deficits are present in affected goats. Thus, a role for reduced thyroid hormone levels in hypomyelination in caprine {dollar}beta{dollar}-mannosidosis is possible.