Publications by authors named "Yaacov Kacher"

A number of studies have shown altered cytokine levels in serum from Gaucher disease patients, including changes in levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the source of IL-10, or the mechanisms leading to changes in IL-10 serum levels are not known. We now show that mouse macrophages treated with an active site-directed inhibitor of glucocerebrosidase, or macrophages from a mouse model of Gaucher disease, the L444P mouse, release significantly less IL-10 than their untreated counterparts, but that TNFalpha release is unaffected.

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In mammalian cells, glucosylceramide (GlcCer), the simplest glycosphingolipid, is hydrolyzed by the lysosomal enzyme acid beta-glucosidase (GlcCerase). In the human metabolic disorder Gaucher disease, GlcCerase activity is significantly decreased owing to one of approximately 200 mutations in the GlcCerase gene. The most common therapy for Gaucher disease is enzyme replacement therapy (ERT), in which patients are given intravenous injections of recombinant human GlcCerase; the Genzyme product Cerezyme has been used clinically for more than 15 years and is administered to approximately 4000 patients worldwide.

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We have recently shown that phosphatidylcholine (PC) metabolism is altered in a macrophage model of Gaucher disease. We now demonstrate that treatment of macrophages with conduritol-B-epoxide (CBE), a glucocerebrosidase inhibitor, results in elevated activity of CTP:phosphocholine cytidylyltransferase (CCT), the rate-limiting enzyme in the pathway of PC biosynthesis. Furthermore, we provide evidence for a role for CCT in Gaucher macrophage growth by using macrophages derived from a genetically modified mouse which lacks a specific CCT isoform, CCTalpha, in macrophages.

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Although diseases in the pathway of sphingolipid degradation have been known for decades, the first disease in the biosynthetic pathway was only reported in 2004, when a form of infantile-onset symptomatic epilepsy was described as a genetic defect in GM3 synthase. Presumably other diseases in the sphingolipid biosynthetic pathway will yet be discovered, although many may remain undetected due to their putative lethal phenotypes. In contrast, diseases are known for essentially every step in the pathway of SL degradation, caused by the defective activity of one or other of the lysosomal hydrolases in this pathway.

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The glycosphingolipid lysosomal storage diseases are a group of monogenic human disorders caused by the impaired catalytic activity of enzymes responsible for glycosphingolipid catabolism. Clinical presentation of the diseases is heterogeneous, with little obvious correlation between the kind of accumulating glycosphingolipid and disease progression or pathogenesis. In this review, we discuss clinical symptoms of this group of diseases, and attempt to link disease progression and pathology with the biochemical and cellular pathways that may be potentially altered in the diseases.

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Glycosphingolipid storage disorders are inborn errors of metabolism caused by the defective activity of degradative enzymes in lysosomes. In this review, we summarize studies performed over the past few years attempting to define the secondary and down-stream biochemical and cellular pathways affected in GSL storage disorders that are responsible for neuronal dysfunction, a characteristic of most of these disorders. We focus mainly on the regulation of intracellular calcium homeostasis and phospholipid biosynthesis.

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