993 research outputs found
Materie, die lebt – Materie, die erlebt. Zur Physik des freien Willens.
No full textCruse H. Materie, die lebt – Materie, die erlebt. Zur Physik des freien Willens. In: Sandhoff K, Donner W, eds. Verhandlungen der Ges. Deutscher Naturforscher u. Ärzte. Stuttgart: Thieme; 2007: 225-235
Iminosugar-based GCS inhibitors improve Sandhoff mouse function.
No full text<p>(<b>A</b>) Mice were evaluated in an open-field assay at 112 days of age. Total distance traversed (ambulatory distance) and the number of times the mice raised onto their hind legs (rearing events) over 30 min are shown. (n = 15/group. Statistics are between untreated and treated Sandhoff mice, and were determined using the Graphpad Prism software t test; ** = p<0.01, *** = p<0.001. Error bars indicate SEM). (<b>B</b>) Mice were evaluated for motor coordination using the rotarod assay. The amount of time (in secs) the mice remained on the rotarod is reported as the latency. Latency is shown for wild-type mice, Genz-529468- and <i>N</i>B-DNJ-treated Sandhoff mice and untreated Sandhoff mice. (n = 15/group). Statistics compared untreated Sandhoff to Genz-529468-treated Sandhoff mice, and were determined using the Graphpad Prism software t test; * = p<0.05, ** = p<0.01, *** = p<0.001. Error bars indicate SEM.</p
The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease
No full textHuman lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3 Angstrom resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset,Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S. (C) 2003 Elsevier Science Ltd. All rights reserved
Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.
No full textThe GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses
Gangliosides are Transported from the Plasma Membrane to Intralysosomal Membranes as Revealed by Immuno-Electron Microscopy
No full textA biotin-labeled derivative of the ganglioside GM1 (biotin-GM1) was used to study its transport along the endocytic pathway of cultured fibroblasts by immuno-electron microscopy. Using electron dense endocytic tracers we could demonstrate that late endosomes and lysosomes of these cells are long living organelles with a high content of internal membranes. Our studies show that during endocytosis the biotin-GM1 was transported to these intraendosomal and intralysosomal membranes. These observations support the hypothesis that glycosphingolipids (GSL) are preferentially degraded in intralysosomal vesicles.A biotin-labeled derivative of the ganglioside GM1 (biotin-GM1) was used to study its transport along the endocytic pathway of cultured fibroblasts by immuno-electron microscopy. Using electron dense endocytic tracers we could demonstrate that late endosomes and lysosomes of these cells are long living organelles with a high content of internal membranes. Our studies show that during endocytosis the biotin-GM1 was transported to these intraendosomal and intralysosomal membranes. These observations support the hypothesis that glycosphingolipids (GSL) are preferentially degraded in intralysosomal vesicles
Sphingolipid activator proteins: proteins with complex functions in lipid degradation and skin biogenesis
No full textCerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation
No full textSandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses
Iminosugar-based GCS inhibitors increase Sandhoff mouse survival.
No full text<p>Mice were monitored daily from 80 days of age and euthanized when they became moribund and were unable to right themselves from a supine position within 30 sec. Untreated mice displayed a median survival of 135 days; Sandhoff mice treated with Genz-5294468 or <i>N</i>B-DNJ had median survivals of 181 days and 191 days, respectively. Both iminosugar-based GCS inhibitors significantly (p<0.0001) increased survival relative to that of untreated Sandhoff mice. (n = 15/group).</p
Neural precursor cell cultures from GM2-gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology
No full textIn this work we showed that genotype-related patterns of hexosaminidase activity, isoenzyme composition, gene expression and ganglioside metabolism observed during embryonic and postnatal brain development are recapitulated during the progressive stages of neural precursor cell (NPC) differentiation to mature glia and neurons in vitro. Further, by comparing NPCs and their differentiated progeny established from Tay-Sachs (TS) and Sandhoff (SD) animal models with the wild-type counterparts, we studied the events linking the accumulation of undegraded substrates to hexosaminidase activity. We showed that similarly to what observed in brain tissues in TS NPCs and progeny, the stored GM2 was partially converted by sialidase to GA2, which can be then degraded in the lysosomes to its components. The latter can be used in a salvage pathway for the formation of GM3. Interestingly, results obtained from ganglioside feeding assays and from measurement of lysosomal sialidase activity suggest that a similar pathway might work also in the SD model
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