DAGLA

更新于：2025-05-07

基本信息

别名

C11orf11、chromosome 11 open reading frame 11、DAGL-alpha

+ [10]

简介

Serine hydrolase that hydrolyzes arachidonic acid-esterified diacylglycerols (DAGs) to produce the principal endocannabinoid, 2-arachidonoylglycerol (2-AG) (PubMed:14610053, PubMed:23502535, PubMed:26668358). Preferentially hydrolyzes sn-1 fatty acids from diacylglycerols (DAG) that contain arachidonic acid (AA) esterified at the sn-2 position to biosynthesize 2-AG (PubMed:14610053, PubMed:23502535, PubMed:26668358). Has negligible activity against other lipids including monoacylglycerols and phospholipids (PubMed:14610053). Plays a key role in regulating 2-AG signaling in the central nervous system (CNS). Regulates 2-AG involved in retrograde suppression at central synapses. Supports axonal growth during development and adult neurogenesis. Plays a role for eCB signaling in the physiological regulation of anxiety and depressive behaviors. Regulates also neuroinflammatory responses in the brain, in particular, LPS-induced microglial activation (By similarity).

关联

100 项与 DAGLA 相关的临床结果

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0 项与 DAGLA 相关的专利（医药）

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123

项与 DAGLA 相关的文献（医药）

2025-05-01·animal

Unravelling novel and closely linked association signals for fat-related traits in pigs using prioritised variants from whole-genome sequence data

Article

作者: Molinero, E ; Pena, R N ; Estany, J ; Ros-Freixedes, R

For most production traits, the largest proportions of genetic variance remain unmapped. Dense whole-genome sequence (WGS) data enable the possibility of discovering novel associations as well as unravelling closely linked association signals with a resolution that marker arrays cannot reach. However, the identification of variants from WGS data that are causal of the variation of complex traits is hindered by the high dimensionality and linkage disequilibrium. Thus, at best, we can narrow the circle around the causal variants to prioritise a set of variants for their posterior validation. In this study, we assessed the utility of WGS data for uncovering associations of weaker effects using, as a model, fat content and composition traits in a Duroc pig population where we previously described major effects of the LEPR and SCD genes. We genotyped 971 pigs for a set of 182 variants from 154 candidate genes that were prioritised from amongst the WGS variants discovered in 205 sequenced individuals. These variants were prioritised conditional to LEPR and SCD. The association of the prioritised variants with the target traits was then tested in the confirmation set of 971 pigs. A total of 17 potentially independent quantitative trait loci (8.4% of the total number of studied genes) were significantly associated (q-value < 0.05) with at least one of the studied traits. We identified novel associations attributable to genes such as ABCC2, MOGAT2, or PLPP1 for backfat thickness, myristic acid content, and monounsaturated fatty acid content, respectively. Our results also revealed a finer granularity of weaker genetic effects in loci such as those around the DGAT2 and FADS2 genes, which may mask the effects of closely located genes like MOGAT2 and DAGLA, respectively. To refine the prioritisation of variants for validation studies, especially when targeting those of weaker effects, we recommend larger and more diverse discovery sets, more precise and complete functional gene annotation, and the integration of other omics data.

2025-02-01·The Journal of Physiology

Inhibition of diacylglycerol lipase α induced blood–brain barrier breach in female Sprague–Dawley rats

Article

作者: Largent‐Milnes, Tally M. ; Couture, Sarah A. ; Liktor‐Busa, Erika ; Pires, Paulo W. ; Anderson, Trent ; Polk, Felipe D. ; Levine, Aidan A. ; Young, Sally J. ; Palomino, Seph M. ; Bader, Colin

AbstractThe endocannabinoid system's significance in maintaining blood–brain barrier (BBB) integrity under physiological and pathological conditions is suggested by several reports, but the underlying molecular mechanisms are not well understood. In this paper, we investigated the effects of depletion of 2‐arachidonoylglycerol (2‐AG), one of the main endocannabinoids in the central nervous system, on BBB integrity using pharmacological tools. Female Sprague–Dawley rats were injected with the diacylglycerol lipase α (DAGLα) inhibitor LEI‐106 (40 mg/kg, i.p.), followed by assessment of BBB integrity via in situ brain perfusion. Liquid chromatography–mass spectrometry, western immunoblotting, light transmittance experiments and pressure myography were also used to further examine the results of DAGLα blockade on the BBB and vascular reactivity. We found that DAGLα inhibition caused BBB opening in cortical brain areas, manifesting as increased sucrose transport measured by in situ brain perfusion. This was accompanied by reduced levels of 2‐AG and decreased detection of the tight junction protein zonula occludens‐1 (ZO‐1). The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity‐dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI‐106 administration. We also observed a significant increase in pressure‐induced constriction within the parenchymal microcirculation after inhibition of DAGLα, possibly altering shear stress in the microcirculation. These results support the role of endogenous 2‐AG in maintaining normal tight junction function. This improved understanding of the molecular mechanisms of endocannabinoid system function at the neurovascular unit can help to unlock the therapeutic potentials of cannabinoids in central nervous system disorders associated with BBB dysfunction.

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Key points

The administration of the diacylglycerol lipase α (DAGLα) inhibitor LEI‐106 (40 mg/kg, i.p.) induced blood–brain barrier (BBB) opening of cortical brain areas in female Sprague–Dawley rats.

This BBB disruption was accompanied by reduced levels of 2‐arachidonoylglycerol (2‐AG) and decreased detection of the tight junction protein zonula occludens‐1 (ZO‐1).

The protein level in cortical areas of neuronal PAS domain protein 4 (NPAS4), encoded by an activity‐dependent immediate early gene, was increased without the presence of cortical spreading depression after LEI‐106 administration.

A significant increase in pressure‐induced constriction within the parenchymal microcirculation was also observed after inhibition of DAGLα, possibly altering shear stress.

These results support the role of endogenous 2‐AG in maintaining normal tight junction function.

2024-11-01·Journal of Neurology, Neurosurgery & Psychiatry

Identification of DAGLA as an autoantibody target in cerebellar ataxia

Article

作者: Hahn, Stefanie ; Guerti, Khadija ; Laureys, Guy ; Schnitter, Linda ; Bien, Corinna Ines ; Sühs, Kurt-Wolfram ; Oyaert, Matthijs ; Specht, Ina ; Rombach, Frederik ; Corty, Merle ; Denno, Yvonne ; van Pesch, Vincent ; Rochow, Nadine ; Nitsch, Sophie ; Probst, Christian ; Scharf, Madeleine ; Teegen, Bianca ; Benkhadra, Farid ; Borowski, Kathrin ; Wattjes, Mike P ; Miske, Ramona ; Komorowski, Lars ; Ratuszny, Dominica ; Wandinger, Klaus-Peter ; Radzimski, Christiane ; Loritz, Monika-Johanna ; Skripuletz, Thomas

BackgroundWe aimed to investigate the clinical, imaging and fluid biomarker characteristics in patients with antidiacylglycerol lipase alpha (DAGLA)-autoantibody-associated cerebellitis.MethodsSerum and cerebrospinal fliud (CSF) samples from four index patients were subjected to comprehensive autoantibody screening by indirect immunofluorescence assay (IIFA). Immunoprecipitation, mass spectrometry and recombinant protein assays were used to identify the autoantigen. Sera from 101 patients with various neurological symptoms and a similar tissue staining pattern as the index patient samples, and 102 healthy donors were analysed in recombinant cell-based IIFA (RC-IIFA) with the identified protein. Epitope characterisation of all positive samples was performed via ELISA, immunoblot, immunoprecipitation and RC-IIFA using different DAGLA fragments.ResultsAll index patients were relatively young (age: 18–34) and suffered from pronounced gait ataxia, dysarthria and visual impairments. Paraclinical hallmarks in early-stage disease were inflammatory CSF changes and cerebellar cortex hyperintensity in MRI. Severe cerebellar atrophy developed in three of four patients within 6 months. All patient samples showed the same unclassified IgG reactivity with the cerebellar molecular layer. DAGLA was identified as the target antigen and confirmed by competitive inhibition experiments and DAGLA-specific RC-IIFA. In RC-IIFA, serum reactivity against DAGLA was also found in 17/101 disease controls, including patients with different clinical phenotypes than the one of the index patients, and in 1/102 healthy donors. Epitope characterisation revealed that 17/18 anti-DAGLA-positive control sera reacted with a C-terminal intracellular DAGLA 583–1042 fragment, while the CSF samples of the index patients targeted a conformational epitope between amino acid 1 and 157.ConclusionsWe propose that anti-DAGLA autoantibodies detected in CSF, with a characteristic tissue IIFA pattern, represent novel biomarkers for rapidly progressive cerebellitis.

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