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At least 739 records · Page 41Linked to original sources
PubMed2005

Principles of lysosomal membrane digestion: stimulation of sphingolipid degradation by sphingolipid activator proteins and anionic lysosomal lipids.

Sphingolipids and glycosphingolipids are membrane components of eukaryotic cell surfaces. Their constitutive degradation takes place on the surface of intra-endosomal and intra-lysosomal membrane structures. During endocytosis, these intra-lysosomal membranes are formed and prepared for digestion by a lipid-sorting process during which their cholesterol content decreases and the concentration of the negatively charged bis(monoacylglycero)phosphate (BMP)--erroneously also called lysobisphosphatidic acid (LBPA)--increases. Glycosphingolipid degradation requires the presence of water-soluble acid exohydrolases, sphingolipid activator proteins, and anionic phospholipids like BMP. The lysosomal degradation of sphingolipids with short hydrophilic head groups requires the presence of sphingolipid activator proteins (SAPs). These are the saposins (Saps) and the GM2 activator protein. Sphingolipid activator proteins are membrane-perturbing and lipid-binding proteins with different specificities for the bound lipid and the activated enzyme-catalyzed reaction. Their inherited deficiency leads to sphingolipid- and membrane-storage diseases. Sphingolipid activator proteins not only facilitate glycolipid digestion but also act as glycolipid transfer proteins facilitating the association of lipid antigens with immunoreceptors of the CD1 family.

Animals↗
PubMed1991

Biochemical basis of late-onset neurolipidoses.

The occurrence and the tremendous phenotypic variability of late-onset neurolipidosis variants are explained on the basis of a simple kinetic model that describes the correlation between residual activity of a deficient lysosomal enzyme and the degradation rate of its substrate in the lysosome.

Adult↗
PubMed1991

The clinical aspects of adult hexosaminidase deficiencies.

The authors describe the clinical phenotypes of hexosaminidase deficiencies (GM2 gangliosidosis). The symptoms, differently combined, include cerebellar ataxia, motor neuron disease, dystonia, psychosis, neurovegetative troubles with different severity. Morphological changes are evident in rectal, muscle or nerve biopsies. Minor clinical changes are described in carriers from a family. A chronic GM2 gangliosidosis has to be suspected in any atypical case with the above-mentioned symptoms with autosomal-recessive inheritance.

Adolescent↗
PubMed1995

Immunological studies on sphingolipid activator proteins in the neuronal ceroid-lipofuscinoses.

The neuronal ceroid-lipofuscinoses constitute an important group of progressive encephalopathies leading to severe psychomotor retardation, blindness, and early death. They are characterized by accumulation of autofluorescent, electron-dense storage bodies within the cytoplasm of neurons and many other cell types. We have recently identified sphingolipid activator proteins A and D as major components of the storage cytosomes in the infantile form of NCL. Using an immunological approach we have shown that sphingolipid activator proteins also constitute an integral component of the storage bodies in the other major forms of the disease.

Blotting, Western↗
PubMed1987

Biochemical heterogeneity in I-cell disease. Sucrose-loading test classifies two distinct subtypes.

Since we observed the normalization of intracellular hydrolases in some cell lines of I-cell disease (ICD) by 88 mmol/l sucrose, we have hypothesized that the degree of responses of the hydrolases might be due to biochemical heterogeneity among ICD. In this study the changes of intracellular lysosomal enzymes as well as Golgi enzymes including N-acetylglucosaminyl phosphotransferase (GlcNAcPTase) and extracellular hexosaminidase (HEX) were investigated using normal and ICD fibroblasts. Sucrose loading induced the activities of intracellular HEX and GlcNAcPTase simultaneously only in responding-type ICD cells, and not in nonresponding-type ICD cells, indicating that two biochemical heterogeneous groups exist in ICD.

Cells, Cultured↗
PubMed1993

Collaborative study of the molecular epidemiology of Tay-Sachs disease in Europe.

Tay-Sachs disease is a lipidosis due to the deficiency of the lysosomal hexosaminidase A. In order to understand the molecular mechanisms of this enzyme deficiency we studied 42 patients of different ethnic origins diagnosed in Europe. The strategy used consists in HEXA cDNA amplification followed by allele-specific oligonucleotide analysis for the frequent mutations, and by chemical cleavage mismatch and denaturing gradient gel electrophoresis for the detection of new mutations. 90% of alleles were clarified in this way, showing a high heterogeneity of HEXA lesions in Tay-Sachs disease. 28 different mutations were found, 20 being identified for the first time in this group of patients.

Adult↗
PubMed1999

Intracellular distribution of a biotin-labeled ganglioside, GM1, by immunoelectron microscopy after endocytosis in fibroblasts.

A radioactive and biotin-labeled analogue of GM1 (biotin-GM1) was synthesized which enabled us to analyze its intracellular distribution in the compartments of the endocytic route by electron microscopic immunocytochemistry using thin sections of human skin fibroblasts labeled with gold-conjugated antibiotin antibodies. Metabolic studies with the biotin-GM1 showed its partial degradation to the corresponding GM2 and GM3 derivatives. Further degradation was inhibited by the biotin residue. The distribution of biotin-GM1 after uptake by cells was studied by postembedding labeling techniques. On the plasma membrane the biotin-GM1 was detectable in the form of patches (0.1 micrometer in diameter), in caveola-like structures and, to a much lesser extent, in coated pits or vesicles. During endocytic uptake, the biotin-GM1 became detectable in organelles identified as late endosomes and lysosomes. The intracellular distribution of the biotin-GM1 was compared to the localization of the EGF receptor in EGF-stimulated fibroblasts. Both the biotin-GM1 and the EGF receptor were transported to intraendosomal and intralysosomal membranes, indicating that both membrane constituents follow the same pathway of endocytosis. Our observations show that biotin-GM1 can be successfully incorporated into the plasma membrane and be used as a tool for morphological detection of its pathway to lysosomes.

Biotin↗
PubMed1979

The gangliosidoses: comparative features and research applications.

Ganglioside storage diseases are inherited defects of lysosomal hydrolases that result in intralysosomal accumulation of gangliosides and other complex metabolites. Gangliosidoses occur in man, cats, cattle, dogs and swine. In all species, these diseases are characterized clinically by relentlessly progressive neurological deterioration. Lysosomal hypertrophy with characteristic ultrastructural inclusions occur in neurons, endothelial and other cells. Definitive diagnosis requires biochemical identification of the storage product and enzyme deficiency. Gangliosidoses in animals are important models of human lysosomal diseases and may be a significant complication in the maintenance of certain purebred stocks of domestic animals.

Animals↗
PubMed1979

Multiangle light scattering flow photometry of cultured human fibroblasts: comparison of normal cells with a mutant line containing cytoplasmic inclusions.

Multi-angle light scattering flow photometry was used to study the light scattering properties of normal cultured fibroblasts and a mutant fibroblast line containing cytoplasmic lysosomal inclusions. The effect of glutaraldehyde fixation on the light scattering properties of the cells was also examined and correlated with their ultrastructure. Normal fibroblasts showed uniform organelle distribution with few vacuoles or dense bodies in the cytoplasm while the mutant line showed abnormal cytoplasmic inclusions of varying morphology, density and lucency. As predicted by light scattering theory, the mutant cells containing the cytoplasmic inclusions scattered more light at large angles (greater than theta = 1.85 degrees) than did the normal cells. Glutaraldehyde fixation decreased light scattering at small angles (less than theta = 1.85 degrees), increased light scattering at larger angles (greater than theta = 1.85 degrees) in both normal and mutant cells and enhanced resolution of the light scattering signatures. The mutant line scattered 2-3 times more light at a wide angle (greater than theta = 12.74 degrees) than did the normal cells. These data suggest that abnormal lysosomal storage inclusion bodies in the cytoplasm of the cells can be detected by differential light scattering methods.

Cell Line↗
PubMed2002

Sphingolipid metabolism during epidermal barrier development in mice.

In rodents, a competent skin barrier to water loss is formed within 2 or 3 days prior to birth. Acquisition of barrier function during rat gestation correlates with the formation of a stratum corneum enriched in ceramides, cholesterol, and fatty acids (Aszterbaum, M., G. K. Menon, K. R. Feingold, and M. L. Williams. 1992. Ontogeny of the epidermal barrier to water loss in the rat: correlation of function with stratum corneum structure and lipid content. PEDIATR: Res. 31: 308-317). We analyzed the formation and epidermal localization of glucosylceramides during embryonic skin barrier development in Balb/c mice. Using immunohistochemistry, epidermal glucosylceramides were hardly detectable 3 days prior to birth. After further 24 h of gestation the level of glucosylceramides was maximal and decreased with increasing gestational age. In parallel, glucosylceramides were targeted to the apical side of the outermost granular keratinocyte layer. A spectrum of five distinct epidermal ceramides was present 2 days prior to birth. With ongoing gestation the composition of the ceramide fraction changed markedly. Most importantly, the level of omega-hydroxylated acylceramides decreased paralleled by the formation of the corneocyte lipid envelope. This structure consists of omega-hydroxylated ceramides and fatty acids bound to surface proteins of the corneocytes. The covalent attachment of ceramides or glucosylceramides correlated with the maturation of the stratum corneum and might contribute to its chemical and enzymatic resistance.

Animals↗
PubMed2005

A novel mass spectrometric assay for the cerebroside sulfate activator protein (saposin B) and arylsulfatase A.

A mass spectrometric method is described for monitoring cerebrosides in the presence of excess concentrations of alkali metal salts. This method has been adapted for use in the assay of arylsulfatase A (ASA) and the cerebroside sulfate activator protein (CSAct or saposin B). Detection of the neutral glycosphingolipid cerebroside product was achieved via enhancement of ionization efficiency in the presence of lithium ions. Assay samples were extracted into the chloroform phase as for the existing assays, dried, and diluted in methanol-chloroform-containing lithium chloride. Samples were analyzed by electrospray ionization mass spectrometry with a triple quadrupole mass spectrometer in the multiple reaction monitoring tandem mass spectrometric mode. The assay has been used to demonstrate several previously unknown or ambiguous aspects of the coupled ASA/CSAct reaction, including an absolute in vitro preference for CSAct over the other saposins (A, C, and D) and a preference for the non-hydroxylated species of the sulfatide substrate over the corresponding hydroxylated species. The modified assay for the coupled ASA/CSAct reaction could find applicability in settings in which the assay could not be performed previously because of the need for radiolabeled substrate, which is now not required.

Animals↗
PubMed1984

Evaluation of possible first trimester prenatal diagnosis in lysosomal diseases by trophoblast biopsy.

The detection of enzymatic deficiency in cultured amniotic cells from second trimester pregnancies is presently used for prenatal diagnosis of lysosomal diseases. The possibility of obtaining and processing trophoblast tissue at 8-10 weeks of gestation would permit first trimester prenatal diagnosis. Using trophoblast tissue samples from normal fetuses before voluntary abortion and from placenta after therapeutic abortions of fetuses affected by several lysosomal diseases, we conclude that early diagnosis of lysosomal disorders would be possible.

Biopsy↗
PubMed1985

Prenatal diagnosis of GM2 gangliosidosis with high residual hexosaminidase A activity (variant B1; pseudo AB variant).

A case of infantile GM2 gangliosidosis with high residual beta-hexosaminidase A activity toward the synthetic substrate 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside was diagnosed prenatally. Extracts from cultured amniotic fluid cells of the fetus had a hexosaminidase A activity of 27% of total hexosaminidase but were almost completely unable to degrade [3H]ganglioside GM2 (less than 0.5% of control values) when assayed in the presence of the natural activator protein. These results were confirmed by analyses of fetal muscle fibroblasts, liver, and brain. All tissues examined showed a profound deficiency of ganglioside GM2 galactosaminidase despite hexosaminidase A levels in the heterozygote range. In brain tissue, ganglioside GM2 content was elevated more than 4-fold. Hydrolysis of p-nitrophenyl glucosaminide-6-sulfate, a substrate specific for hexosaminidases A and S, by tissue extracts was also markedly reduced but the residual activities found (5% in liver, 12% in fibroblasts, and 16% in brain) were much higher than those with the physiological lipid substrate, ganglioside GM2.

Amniocentesis↗