g(m2)-ganglioside and Gaucher-Disease

Lysosomal storage diseases (LSDs), of which about 50 are known, are caused by the defective activity of lysosomal proteins, resulting in accumulation of unmetabolized substrates. As a result, a variety of pathogenic cascades are activated such as altered calcium homeostasis, oxidative stress, inflammation, altered lipid trafficking, autophagy, endoplasmic reticulum stress, and autoimmune responses. Some of these pathways are common to many LSDs, whereas others are only altered in a subset of LSDs. We now review how these cascades impact upon LSD pathology and suggest how intervention in the pathways may lead to novel therapeutic approaches.

Topics: Antigens, CD; Autoimmune Diseases; Autophagy; Calcium; Endoplasmic Reticulum; Free Radicals; G(M2) Ganglioside; G(M3) Ganglioside; Gaucher Disease; Humans; Lactosylceramides; Lysosomal Storage Diseases; Lysosomes; Mitochondria; Oxidative Stress

Lysosomal storage diseases are clinically heterogeneous with respect to their age of onset, progression of symptoms and the particular organs involved. Varying levels of residual enzyme activity, associated with different defective alleles that cause the respective diseases, are responsible in part for this clinical heterogeneity. In general, the higher the residual enzyme activity, the milder the phenotype. Enzyme activity in severe forms of disease is frequently zero, and in mild forms usually does not exceed approximately 5%. However, the correlation is not so strict as to allow prediction of the phenotype of individual patients. The molecular basis of the different levels of enzyme activity can only be revealed by biochemical investigations of the defective lysosomal proteins. Null alleles may be due to splice-site mutations or deletions. In the case of missense mutations, enzymes frequently fold incorrectly and are retained in the endoplasmic reticulum and subsequently degraded. As these enzymes do not reach the lysosome, they do not provide any functional residual activity. Residual enzyme activity is only observed in cases where the defective enzyme reaches the lysosome and has retained enzymatic activity. Patients carrying the same mutant alleles still show considerable phenotypic variability due to modifying genes and epigenetic factors. None of these has so far been elucidated. However, there are some indications that differences in splicing-factor machinery may influence the phenotypic expression of splice-site mutations and that hormonal modulation of secondary microglial activation in lipidosis may also influence the disease course.. Phenotypic variability is a frequent phenomenon in lysosomal storage diseases. Residual enzyme activity has been identified as one of the factors influencing the clinical outcome of disease; however, it is obvious that other genetic and epigenetic factors also affect phenotypic variability, particularly in patients with late onset disease.

Topics: Alleles; DNA, Recombinant; Endoplasmic Reticulum; G(M2) Ganglioside; Gangliosidoses, GM2; Gaucher Disease; Humans; Leukodystrophy, Metachromatic; Lysosomal Storage Diseases; Phenotype; Point Mutation; Tay-Sachs Disease

Most lysosomal storage disorders are known as pediatric diseases. In recent years late onset and adult forms of these disorders have been recognized. The adult form of a given lysosomal storage disorder differs from the childhood disease in several respects. Adult disorders are, with some exceptions, less common than the childhood diseases. The clinical picture is not only less severe, but often shows quite different clinical signs and symptoms than the early onset form. Metachromatic leucodystrophy, GM1 and GM2 gangliosidoses, Gaucher disease and aspartylglucosaminuria are presented as examples of lysosomal storage disorders manifesting as adult diseases. The differences of the early and late onset disorders are discussed in the light of recent results of molecular genetics, residual enzyme activity and pseudodeficiency.

Topics: Acetylglucosamine; Adult; Age of Onset; Aspartylglucosaminuria; G(M2) Ganglioside; Gangliosidoses; Gangliosidosis, GM1; Gaucher Disease; Humans; Leukodystrophy, Metachromatic

Topics: Adolescent; Adult; Animals; beta-Galactosidase; Cats; Cerebrovascular Disorders; Child, Preschool; Coronary Disease; Fabry Disease; Female; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycolipids; Hexosaminidases; Humans; Infant; Infant, Newborn; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Male; Sodium-Potassium-Exchanging ATPase; Vascular Resistance

Topics: Animals; Cats; Cattle; Disease Models, Animal; Dogs; G(M2) Ganglioside; Gangliosidoses; Gaucher Disease; Glycogen; Glycogen Storage Disease Type II; Glycopeptides; Humans; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Lipidoses; Lysosomes; Mannosidases; Metabolism, Inborn Errors; Mice; Niemann-Pick Diseases; Rabbits; Sphingolipids

The lipids accumulated in organs of patients with Gaucher's, Tay-Sachs, and Fabry's disease were identified by means of the combination of thin-layer chromatography and matrix-assisted secondary ion mass spectrometry. The total lipid extract of each lipidosis tissue was chromatographed on a TLC plate and then analyzed directly by mass spectrometry without elution of the sample from the TLC plate. The amount of material needed to obtain an adequate spectrum is in the order of a few micrograms of lipids per band for both positive and negative ion detection. By scanning the plates, mass spectral and chromatographic information can be obtained simultaneously, which was shown to be useful for the qualitative identification of the components on the plates.

Topics: Chromatography, Thin Layer; Fabry Disease; G(M2) Ganglioside; Gaucher Disease; Globosides; Glucosylceramides; Glycolipids; Humans; Mass Spectrometry; Sphingolipidoses; Tay-Sachs Disease; Trihexosylceramides

1. A third beta-glucosidase from human liver has been isolated using a mild (0.02-0.10%) Triton X-100 extraction of the exhaustively washed high speed (200,000 X g, 30 min) particulate fraction, QAE-Sephadex and concanavalin A-Sepharose chromatography. This new beta-glucosidase, referred to as TX beta-glucosidase, possesses a distinctive set of chemical properties such that it is similar to both, glucocerebrosidase and cytoplasmic beta-glucosidase, but it is not identical to either enzyme. 2. The TX beta-glucosidase hydrolyzes glucocerebroside as well as the beta-D-glucose, beta-D-galactose, beta-D-fucose, beta-D-xylose and alpha-L-arabinose derivatives of 4-methylumbelliferone. Like the cytoplasmic beta-glucosidase, the TX beta-glucosidase is inhibited by bile salts, and unaffected by conduritol B epoxide and heat stable activator protein. 3. All three beta-glucosidases were inhibited by N-hexylpsychosine, and all showed the same, mixed type inhibition kinetics, indicating a common hydrophobic binding site in all three enzymes. 4. The TX beta-glucosidase, which constitutes only a few percent of the total beta-glucosidase activity of human liver, is absent from liver from two cases of neurologic Gaucher disease and present in reduced amounts in a third case with CNS disease. Liver from a case of type 1 Gaucher disease contained normal amounts of the TX beta-glucosidase.

Topics: beta-Glucosidase; Bile Acids and Salts; Enzyme Activation; G(M2) Ganglioside; Gaucher Disease; Glucosidases; Glucosylceramidase; Humans; Isoenzymes; Liver; Substrate Specificity

Topics: Adult; beta-Glucosidase; Cells, Cultured; Enzyme Activation; Fibroblasts; G(M1) Ganglioside; G(M2) Ganglioside; Gangliosides; Gaucher Disease; Glucosidases; Hot Temperature; Humans; Isoelectric Focusing; Male; Skin