Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells subjected to glycated collagen I develop premature senescence within 3-5 days, as revealed by increased senescence-associated beta-galactosidase activity, decreased proliferation, and an increase in cell size. Here, we analyzed the time course and possible mechanisms of this process. Lysosomal integrity studies revealed a rapid collapse of pH gradient and lysosomal permeabilization, detectable after 30 min, and preceded by the increased production of reactive oxygen species. Measurement of mitochondrial membrane potential after application of glycated collagen demonstrated that depolarization was delayed by 4 h compared with changes in lysosomal pH and permeability. Based on the above findings of lysosomal permeabilization, we hypothesized that the reduced activity of senescence-associated beta-galactosidase could be responsible for the cellular accumulation of gangliosides, previously shown to induce cell senescence. After 5 days of exposure to glycated collagen, there was an increase in the levels of gangliosides GM3, GD1b, and GT1b, coincident with development of cell senescence. Treatment of endothelial cells with d-threo-EtDOP4, an inhibitor of glucosylceramide synthase, inhibited apoptosis, but not the development of senescence. In conclusion, collagen I modified by advanced glycation initially induces apoptosis of human umbilical vein endothelial cells. This process is initiated by the collapse of lysosomal pH and an increase in lysosomal permeability, with the subsequent mitochondrial depolarization and accumulation of gangliosides. Blockade of ganglioside synthesis suppresses apoptosis, but not senescence, which develops after 3 days of exposure to glycated collagen. These data imply a critical role for lysosomal permeabilization in triggering apoptosis of endothelial cells exposed to the diabetic milieu.
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PMID:Mapping mechanisms and charting the time course of premature cell senescence and apoptosis: lysosomal dysfunction and ganglioside accumulation in endothelial cells. 1792 15

GM1 gangliosidosis is an inherited neurodegenerative disorder caused by lysosomal beta-galactosidase deficiency, resulting in the storage of GM1 and GA1, primarily in the central nervous system. This disease typically afflicts infants and young children and there is currently no effective therapy. Substrate reduction therapy (SRT) could be of potential benefit. The imino sugars N-butyldeoxynojirimycin (NB-DNJ, miglustat, Zavesca) and N-butyldeoxygalactonojirimycin (NB-DGJ) used for SRT inhibit glucosylceramide synthase (GlcCerS) that catalyses the first committed step in glycosphingolipid biosynthesis. We have compared the efficacy and tolerability of NB-DNJ and NB-DGJ in the beta-galactosidase knockout mouse. NB-DGJ was better tolerated than NB-DNJ, due to intrinsic gastrointestinal tract dysfunction that was exacerbated by NB-DNJ. However, functional improvement was greatest with NB-DNJ treatment which may potentially be caused by novel anti-inflammatory properties of NB-DNJ.
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PMID:Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis. 1838 28