Selective reduction of bis(monoacylglycero)phosphate ameliorates the storage burden in a THP-1 macrophage model of Gaucher disease

Abstract

esterifi ed with fatty acids. The stereochemical confi guration of BMP differs as each glycerol moiety is esterifi ed through only the sn 1 position to the phosphate and contains a single fatty acid ( 1 ). Evidence suggests that BMP is synthesized from its structural isomer, phosphatidylglycerol ( 2 ). The fatty acid from the sn 2 position is removed with phospholipase A2 to produce lysophosphatidylglycerol, which then undergoes a transacylation reaction on the sn 2 position of the glycerol head group ( 3, 4 ). The subsequent steps, which must remove the fatty acid from the sn 1 position, rearrange the phosphoryl ester from the sn 3 to the sn 1 position and esterify the sn 2 position to produce the fi nal product, BMP, have not yet been adequately described. The synthesis of BMP is believed to occur in the lysosomal network, as BMP is highly enriched in the internal membranes of lysosomes ( 5 ).The negative charge of BMP, coupled with its proposed cone-shaped structure, enables it to participate in the organization of the membranes of the lysosomal network, contributing to its multivesicular/multilamellar morphology ( 6, 7 ). These properties of BMP also facilitate lysosomal lipid degradation, which takes place on the surface of the inner membranes of lysosomes. At the acidic pH of the lysosome, BMP contributes its negative charge to enhance adherence of the polycationic enzymes and activator proteins, aiding in lipid hydrolysis ( 8 ). Together, the high BMP and low cholesterol content of the internal lysosomal membrane ensures the selective degradation of lipids destined for lysosomal degradation without affecting the limiting membrane of the lysosome ( 9 ). Bis(monoacylglycero)phosphate (BMP) belongs to the group of glycerophospholipids that consist of a glycerol-3-phosphate backbone whose sn 1 and sn 2 positions are

Explorative Combined Lipid and Transcriptomic Profiling of Substantia Nigra and Putamen in Parkinson’s Disease

“…Lipid BMP 42:8 belongs to a lipid class highly enriched in lysosomal membranes [56] and is key for the proper functioning of lysosomal hydrolases [57]. Interestingly, BMP accumulation also occurs in macrophages from patients with Gaucher disease [58], a rare genetic disorder characterized by deposition of the lipid glucocerebroside in macrophages and that highly increases the life-time risk to develop PD [59]. Nevertheless, we realize that it is difficult to draw functional conclusions concerning individual lipids since the number of samples employed in this proof-of-concept study is relatively small and only the roles of lipid classes have been characterized.…”

Functional Diversification and Specialization of Cytosolic 70-kDa Heat Shock Proteins

“…For example, the concentration of BMP in the late endosome is ~15 mol % of the total lipid content of the organelle and can comprise as much as 70 mol % of the lipid composition of the intraendosomal vesicles 42 47 . Furthermore, the concentration, localization, and saturation levels of particular lipids are altered in particular cell types (e.g., red-blood cells 48 49 ), or because of stress (e.g., heat-shock), disease (e.g., cancer, Gaucher, Niemann-Pick), or during apoptosis 29 40 50 51 52 53 54 55 56 . These changes in membrane topography and lipid/protein ratios may facilitate the interaction of Hsp70s with lipids.…”

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

“…BMP becomes limiting in Niemann-Pick disease fibroblasts, and exogenous feeding of BMP decreases excessive cholesterol storage ( 65 ). Also Hein, Duplock, and Fuller ( 15 ) show that selective decrease of BMP reduces the storage material, glucosylceramide, in THP-1 Gaucher macrophages. Further studies will be needed to determine whether modulation of BMP levels can decrease ganglioside storage in the GM1 and GM2 gangliosidoses.…”