The Experts below are selected from a list of 9684 Experts worldwide ranked by ideXlab platform
Alexander Lossos - One of the best experts on this subject based on the ideXlab platform.
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polyglucosan neurotoxicity caused by glycogen branching Enzyme deficiency can be reversed by inhibition of glycogen synthase
Journal of Neurochemistry, 2013Co-Authors: Or Kakhlon, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Hasan O Akman, Alexander LossosAbstract:Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that glycogen branching Enzyme Repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of glycogen branching Enzyme in neurons led to accumulation of an insoluble form of glycogen called polyglucosan, to apoptosis and to activation of glycogen synthase. These effects were reversed by glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of glycogen synthase inhibition for treating glycogen storage disorders.
Or Kakhlon - One of the best experts on this subject based on the ideXlab platform.
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polyglucosan neurotoxicity caused by glycogen branching Enzyme deficiency can be reversed by inhibition of glycogen synthase
Journal of Neurochemistry, 2013Co-Authors: Or Kakhlon, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Hasan O Akman, Alexander LossosAbstract:Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that glycogen branching Enzyme Repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of glycogen branching Enzyme in neurons led to accumulation of an insoluble form of glycogen called polyglucosan, to apoptosis and to activation of glycogen synthase. These effects were reversed by glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of glycogen synthase inhibition for treating glycogen storage disorders.
Markus Grompe - One of the best experts on this subject based on the ideXlab platform.
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176. An Inhibitor of Fumarylacetoacetate Hydrolase (Fah) for Selection of Transplanted Hepatocytes and Gene Correction In Vivo
Molecular Therapy, 2006Co-Authors: Karsten Wursthorn, John F. Witte, Raynard L. Bateman, Milton J. Finegold, Ronald W. Mcclard, Markus GrompeAbstract:Mice deficient in the tyrosine catabolic Enzyme Fah are an excellent model for liver repopulation by selection. Fah positive cells from several different origins can engraft and correct the phenotype of a Fah-mutant liver. Non-cell based gene therapy leading to the in situ correction of the Fah-deficiency also works and repopulation levels of >90% are routinely achieved. Thus, hepatic Fah deficiency provides a powerful in vivo selection environment for cells genetically resistant to the Enzyme deficiency. In order to mimic the same selective pressure in animals not genetically deficient in Fah, we developed a small molecule inhibitor of Fah. 4-[(2-carboxyethyl)- hydroxyphosphinyl]-3-oxobutyrate (CEHPOBA) has a nanomolar Ki for Fah and was injected intraperitoneally into C57/BL6 mice at a concentration of 1|[mu]|moles per gram body weight. In a first round of experiments, the duration of Fah inhibition in vivo was tested. We found that a once-daily injection resulted in a lasting Enzyme Repression. Next, we tested if transplanted hepatocytes could be selected under continuous CEHPOBA administration. As shown previously, hepatocytes mutant for the homogentisic acid dioxygenase (Hgd) an Enzyme upstream of Fah in tyrosine catabolism are able to repopulate the livers of mice with Fah-deficiency. We therefore transplanted 500,000 sex-mismatched Hgd-mutant hepatocytes into Fah+ C57/BL6 mice and concomitantly started CEHPOBA treatment. Treated animals appeared healthy and displayed no major side-effects. After 4 weeks of daily CEHPOBA injection, the livers were harvested and analyzed by semi-quantitative PCR and histology for the presence of Y-chromosome. 1|[ndash]|10% of total hepatocytes were Y-chromosome positive. Transplanted, Y-chromosome positive hepatocytes displaying Fah wild type formed nodules proving clonal expansion and ongoing selection of the genetically favored hepatocytes. Our results show that a significant selection of genetically resistant hepatocytes can be achieved by CEHPOBA administration in vivo. This proof-of-principle opens the door to a whole new field of experimental and therapeutic options for cell transplantation and gene correction of liver diseases in vivo. CEHPOBA resistance occurs in cells lacking Enzymes upstream of Fah in tyrosine metabolism and could therefore be achieved by shRNAs targeting these genes. This strategy is currently under investigation.
Hava Glickstein - One of the best experts on this subject based on the ideXlab platform.
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polyglucosan neurotoxicity caused by glycogen branching Enzyme deficiency can be reversed by inhibition of glycogen synthase
Journal of Neurochemistry, 2013Co-Authors: Or Kakhlon, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Hasan O Akman, Alexander LossosAbstract:Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that glycogen branching Enzyme Repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of glycogen branching Enzyme in neurons led to accumulation of an insoluble form of glycogen called polyglucosan, to apoptosis and to activation of glycogen synthase. These effects were reversed by glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of glycogen synthase inhibition for treating glycogen storage disorders.
Naomi Feinstein - One of the best experts on this subject based on the ideXlab platform.
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polyglucosan neurotoxicity caused by glycogen branching Enzyme deficiency can be reversed by inhibition of glycogen synthase
Journal of Neurochemistry, 2013Co-Authors: Or Kakhlon, Hava Glickstein, Naomi Feinstein, Otto Baba, Tatsuo Terashima, Hasan O Akman, Alexander LossosAbstract:Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching Enzyme 1 (GBE1, EC 2.4.1.18) expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC 2.4.1.11), dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that glycogen branching Enzyme Repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. Knockdown of glycogen branching Enzyme in neurons led to accumulation of an insoluble form of glycogen called polyglucosan, to apoptosis and to activation of glycogen synthase. These effects were reversed by glycogen synthase inhibition through starvation and rapamycin treatments, suggesting a potential therapeutic value of glycogen synthase inhibition for treating glycogen storage disorders.