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.lipidomics | neuroinflammation G enome mapping and sequencing have facilitated determination of the genetic basis for over 3,500 inherited diseases in humans (1), with additional pathogenic mutations still being discovered. For many Mendelian disorders, however, the molecular and cellular mechanisms that link genotype to disease phenotype remain poorly understood. This problem is perhaps most apparent for diseases where the causative mutations occur in genes that encode for proteins with unannotated or poorly characterized functions. Here, we focus on one such disease -the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis pigmentosa, and cataract).PHARC [Mendelian Inheritance in Man (MIM) no. 612674; Online Mendelian Inheritance in Man database, http://omim.org] is a rare, autosomal recessive disorder that causes polymodal sensory and motor defects associated with demyelination of sensomotor neurons, retinal dystrophy, and cerebellar atrophy (2). PHARC symptoms are slowly progressive and begin in the childhood or teenage years; heterozygous carriers are unaffected (3). In 2010, PHARC was reported to be caused by homozygous mutations in ABHD12, which codes for the poorly characterized serine hydrolase enzyme α/β-hydrolase domain-containing (ABHD)12 (3). To date, five distinct ABHD12 mutations have been identified in patients with PHARC, all of which are expected to lead to complete loss of ABHD12 expression (3, 4). PHARC, therefore, likely represents a human ABHD12 null model.We demonstrated previously that ABHD12 is a membranebound e...

Type IV P-type ATPases Distinguish Mono- versus Diacyl Phosphatidylserine Using a Cytofacial Exit Gate in the Membrane Domain

“…Additionally, it is becoming increasingly apparent that lyso-PL species are involved in signaling events. Recent work has implicated the accumulation of long-chain lyso-PS species in a mammalian neurodegenerative condition (42). Lyso-PC is an early metabolic serum marker for diabetes (43) and also serves as a signaling lipid in plants, enhancing responsiveness for a Na ϩ activated H ϩ channel (44) and activating the plasma membrane proton pump AHA2 (45).…”

The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase

“…ABPP and substrate assays of mouse brain and transfected cell lysates were performed as described previously (37). Metabolomic and proteomic analyses of brain homogenates and cell lines were performed as described previously (37) and in SI Appendix, SI Materials and Methods.…”

Metabolomic strategies to map functions of metabolic pathways

“…2A). Blankman et al went further to show that LPS accumulation in the brains of ABHD12-deficient mice led to neuroinflammation by activation of toll-like receptor 2, leading to microglial activation and motor and auditory defects reminiscent of PHARC (3). This work on ABHD12 shows that untargeted metabolomics can be used to implicate unexpected pathways in disease towards linking genotypes to phenotypes.…”

“…Blankman et al (3) recently uncovered the function of the previously uncharacterized enzyme ␣/␤-hydrolase domaincontaining 12 (ABHD12), a serine hydrolase that was muta-tionally inactivated in patients with the neurodegenerative disorder PHARC (polyneuropathy, hearing loss, ataxia, retinosis, pigmentosa, and cataract). Blankman and colleagues generated ABHD12 Ϫ/Ϫ mice, which present the PHARC phenotype, to use in metabolomic studies for mechanistic understanding of ABHD12 in PHARC.…”