ABSTRACT
Bis(monoacylglycero)phosphate (BMP) is a structural isomer of phosphatidylglycerol (PtdGro) with an unusual sn-1:sn-1' fatty acyl configuration and is found almost exclusively in late endosomes/lysosomes. BMP comprises only about 1-2% of the total phospholipids in most mammalian cells, but accumulates in tissues of humans and animals with lysosomal storage disorders including the gangliosidoses. Total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin. BMP composition was similar in tumorigenic/metastatic macrophages and non-tumorigenic macrophages/microglia. Finally, BMP fatty acid composition differed between cells grown in culture and obtained in vivo suggesting an influence from growth environment.
Subject(s)
Lysophospholipids/chemistry , Macrophages/chemistry , Monoglycerides/chemistry , Phospholipids/chemistry , Animals , Cell Line, Tumor , Humans , MiceABSTRACT
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 ß-galactosidase or ß-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.
Subject(s)
Cat Diseases/metabolism , Gangliosidosis, GM1/veterinary , Lysophospholipids/metabolism , Monoglycerides/metabolism , Sandhoff Disease/veterinary , Animals , Brain/metabolism , Cats , Female , Gangliosidosis, GM1/metabolism , Humans , Lipid Metabolism , Male , Mice, 129 Strain , Mice, Knockout , Sandhoff Disease/metabolism , UrsidaeABSTRACT
Most malignant brain tumours contain various numbers of cells with characteristics of activated or dysmorphic macrophages/microglia. These cells are generally considered part of the tumour stroma and are often described as TAM (tumour-associated macrophages). These types of cells are thought to either enhance or inhibit brain tumour progression. Recent evidence indicates that neoplastic cells with macrophage characteristics are found in numerous metastatic cancers of non-CNS (central nervous system) origin. Evidence is presented here suggesting that subpopulations of cells within human gliomas, specifically GBM (glioblastoma multiforme), are neoplastic macrophages/microglia. These cells are thought to arise following mitochondrial damage in fusion hybrids between neoplastic stem cells and macrophages/microglia.
