Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses

Abstract

Bis(monoacylglycero)phosphate (BMP) is a negatively charged glycerophospholipid with an unusual sn-1;sn-1' structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. Elevated BMP levels have been found in many lysosomal storage diseases (LSDs), suggesting an association with lysosomal storage material. The gangliosidoses are a group of neurodegenerative LSDs involving the accumulation of either GM1 or GM2 gangliosides resulting from inherited deficiencies in β-galactosidase or β-hexosaminidase, respectively. Little information is available on BMP levels in gangliosidosis brain tissue. Our results showed that the content of BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. The storage of BMP and ganglioside GM2 in brain were reduced similarly following adeno-associated viral-mediated gene therapy in Sandhoff disease mice. We also found that C22:6, C18:0, and C18:1 were the predominant BMP fatty acid species in gangliosidosis brains. The results show that BMP accumulates as a secondary storage material in the brain of a broad range of mammals with gangliosidoses.

Keywords: GM1-gangliosidosis; Sandhoff disease; brain lipids; fatty acid; gangliosides; gene therapy; lysosomal; phospholipids; storage diseases.

Fig. 1.

Structure of 2,2′ diacyl-sn-1:sn-1′ BMP as previously described (56).

Fig. 2.

HPTLC analysis of acidic lipids in the brains of mice, cats, humans, and bears with ganglioside storage disease. The normal (N), Sandhoff disease (SD), and GM1 mice represent the Hexβ (+/−), Hexβ (−/−), and β-gal (−/−) mice, respectively. The HPTLC was developed for 5 min with chloroform:methanol:ammonia (30% aqueous solution) (65:35:5, v/v/v). The amount of acidic lipid spotted per lane was equivalent to 200 μg of tissue dry weight. The bands were visualized by charring with 3% cupric acetate in 8% phosphoric acid solution. Std, standard is a mixture of purified acidic lipids including BMP, cardiolipin (CL), phosphatidic acid (PA), sulfatides (SULF), phosphatidylserine (PS), and phosphatidylinositol (PI).