lysophosphatidylserine and Polyneuropathies

Mutations in alpha/beta-hydrolase domain containing (ABHD) 12 gene, which encodes lysophosphatidylserine (LysoPS) lipase, cause the neurodegenerative disease PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa, Cataract). Since ABHD12 is expressed by microglia in the central nervous system and is localized to the endoplasmic reticulum, accumulation of intracellular LysoPS by ABHD12 mutations is assumed to be one of the pathological mechanisms associated with microglial activation in PHARC. However, the role of microglia in the PHARC brain and the relationship between microglial function and cellular LysoPS content remains unclear. Therefore, we explored the influence of cellular LysoPS content in microglial inflammatory responses. We evaluated the effects of inhibitors of cellular LysoPS metabolism, KC01 and DO-264, on inflammatory responses using a lipopolysaccharide (LPS)-stimulated mouse microglial cell line, BV-2 and primary microglia. Treatment of DO-264, an inhibitor of cellular LysoPS degradation, enhanced LPS-induced phagocytosis concomitant with the increase in cellular LysoPS content in BV-2 cells. On the other hand, treatment with KC01, an agent had been developed as an inhibitor of LysoPS synthase, reduced phagocytosis without affecting cellular LysoPS content. Such effects of both inhibitors on phagocytosis were also confirmed using primary microglia. KC01 treatment decreased nitric oxide (NO) production, accompanied by a reduction in inducible NO synthase expression in BV-2 microglia. KC01 also suppressed LPS-induced generation of intracellular reactive oxygen species and cytokines such as interleukin-6. Our results suggest that increase in cellular LysoPS levels can exacerbate microglial inflammatory responses. Treatment to prevent the increase in cellular LysoPS in microglia may have therapeutic potential for PHARC.

Topics: Animals; Ataxia; Cataract; Lipopolysaccharides; Lysophospholipids; Mice; Microglia; Monoacylglycerol Lipases; Neurodegenerative Diseases; Nitric Oxide; Nitric Oxide Synthase Type II; Polyneuropathies; Retinitis Pigmentosa

Lysophosphatidylserine (lyso-PS), a lysophospholipid derived from phosphatidylserine (PS), has emerged as a potent signaling lipid in mammalian physiology.

Topics: Animals; Ataxia; Cataract; Cell Line; Cerebellum; Humans; Lysophospholipids; Mice; Mice, Knockout; Monoacylglycerol Lipases; Polyneuropathies; Retinitis Pigmentosa

Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is a rare genetic human neurological disorder caused by null mutations to the

Topics: Animals; Ataxia; Brain; Cataract; Humans; Kinetics; Lipids; Lysophospholipids; Mice; Mice, Knockout; Monoacylglycerol Lipases; Polyneuropathies; Retinitis Pigmentosa; Substrate Specificity

Advances in human genetics are leading to the discovery of new disease-causing mutations at a remarkable rate. Many such mutations, however, occur in genes that encode for proteins of unknown function, which limits our molecular understanding of, and ability to devise treatments for, human disease. Here, we use untargeted metabolomics combined with a genetic mouse model to determine that the poorly characterized serine hydrolase α/β-hydrolase domain-containing (ABHD)12, mutations in which cause the human neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract), is a principal lysophosphatidylserine (LPS) lipase in the mammalian brain. ABHD12(-/-) mice display massive increases in a rare set of very long chain LPS lipids that have been previously reported as Toll-like receptor 2 activators. We confirm that recombinant ABHD12 protein exhibits robust LPS lipase activity, which is also substantially reduced in ABHD12(-/-) brain tissue. Notably, elevations in brain LPS lipids in ABHD12(-/-) mice occur early in life (2-6 mo) and are followed by age-dependent increases in microglial activation and auditory and motor defects that resemble the behavioral phenotypes of human PHARC patients. Taken together, our data provide a molecular model for PHARC, where disruption of ABHD12 causes deregulated LPS metabolism and the accumulation of proinflammatory lipids that promote microglial and neurobehavioral abnormalities.

Topics: Animals; Ataxia; Behavior, Animal; Brain; Cataract; Disease Models, Animal; Humans; Lipid Metabolism; Lysophospholipids; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Models, Neurological; Monoacylglycerol Lipases; Mutation; Phenotype; Polyneuropathies; Retinitis Pigmentosa