title: ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC.
abstract: 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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Departments of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Jonathan Z
authors.initials: JZ
authors.lastname: Long
authors.forename: Sunia A
authors.initials: SA
authors.lastname: Trauger
authors.forename: Gary
authors.initials: G
authors.lastname: Siuzdak
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002386:Cataract / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D006801:Humans; D050356:Lipid Metabolism; D008246:Lysophospholipids / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D008959:Models, Neurological; D008994:Monoacylglycerol Lipases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D011115:Polyneuropathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D008246:Lysophospholipids; C025059:lysophosphatidylserine; C552558:ABHD12 protein, human; C527260:Abhd12 protein, mouse; D008994:Monoacylglycerol Lipases