Sanchez-Alavez M

References (3)

Title : A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation - Viader_2016_Elife_5_
Author(s) : Viader A , Ogasawara D , Joslyn CM , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Cravatt BF
Ref : Elife , 5 : , 2016
Abstract : Metabolic specialization among major brain cell types is central to nervous system function and determined in large part by the cellular distribution of enzymes. Serine hydrolases are a diverse enzyme class that plays fundamental roles in CNS metabolism and signaling. Here, we perform an activity-based proteomic analysis of primary mouse neurons, astrocytes, and microglia to furnish a global portrait of the cellular anatomy of serine hydrolases in the brain. We uncover compelling evidence for the cellular compartmentalization of key chemical transmission pathways, including the functional segregation of endocannabinoid (eCB) biosynthetic enzymes diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) to neurons and microglia, respectively. Disruption of DAGLbeta perturbed eCB-eicosanoid crosstalk specifically in microglia and suppressed neuroinflammatory events in vivo independently of broader effects on eCB content. Mapping the cellular distribution of metabolic enzymes thus identifies pathways for regulating specialized inflammatory responses in the brain while avoiding global alterations in CNS function.
ESTHER : Viader_2016_Elife_5_
PubMedSearch : Viader_2016_Elife_5_
PubMedID: 26779719

Title : Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition - Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
Author(s) : Ogasawara D , Deng H , Viader A , Baggelaar MP , Breman A , den Dulk H , van den Nieuwendijk AM , Soethoudt M , van der Wel T , Zhou J , Overkleeft HS , Sanchez-Alavez M , Mori S , Nguyen W , Conti B , Liu X , Chen Y , Liu QS , Cravatt BF , van der Stelt M
Ref : Proc Natl Acad Sci U S A , 113 :26 , 2016
Abstract : Diacylglycerol lipases (DAGLalpha and DAGLbeta) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLalpha is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.
ESTHER : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedSearch : Ogasawara_2016_Proc.Natl.Acad.Sci.U.S.A_113_26
PubMedID: 26668358
Gene_locus related to this paper: human-DAGLA , human-DAGLB

Title : Monoacylglycerol Lipase Regulates Fever Response - Sanchez-Alavez_2015_PLoS.One_10_e0134437
Author(s) : Sanchez-Alavez M , Nguyen W , Mori S , Moroncini G , Viader A , Nomura DK , Cravatt BF , Conti B
Ref : PLoS ONE , 10 :e0134437 , 2015
Abstract : Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1beta-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.
ESTHER : Sanchez-Alavez_2015_PLoS.One_10_e0134437
PubMedSearch : Sanchez-Alavez_2015_PLoS.One_10_e0134437
PubMedID: 26287872