Glucosylceramide modulates endolysosomal pH in Gaucher disease.

[gm1 gangliosidosis]

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

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Diseases presenting "reduction therapy utilises inhibitors" symptom

gm1 gangliosidosis

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