Glucosylceramide modulates endolysosomal pH in Gaucher disease

摘要: Abstract GlcCer accumulation causes Gaucher disease where breakdown is inhibited due to a hereditary deficiency in glucocerebrosidase. Glycolipids are endocytosed and targeted the Golgi apparatus normal cells but they mistargeted lysosomes. To better understand role of endocytic sorting RAW macrophages were treated with Conduritol B-epoxide inhibit breakdown. Lipid analysis found increases led both triacylglycerol cholesterol consistent increased lysosomal pH. Ratio imaging using acridine orange lysosensor yellow/blue measure endolysosomal pH revealed patient lymphoblasts. Increased was restricted lymphoblasts as no significant seen Fabry, Krabbe, Tay–Sachs GM1-gangliosidosis Substrate reduction therapy utilises inhibitors synthase reduce storage disease. The addition synthesis also an increase up 1 unit. modulation appears specific since glucosylsphingosine not galactosylsphingosine reversed effects depletion. Although acute on glycolipid trafficking observed bafilomycin A results multistep model whereby lead altered via accumulation. modulates lymphocytes suggesting important lysosomes which may be disrupted