A chemical proteomic atlas of brain serine hydrolases identifies cell type-specific pathways regulating neuroinflammation

ELife
Andreu ViaderBenjamin F Cravatt

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 (DAGLα) and -beta (DAGLβ) to neurons and microglia, respectively. Disruption of DAGLβ 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.

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Citations

Jul 12, 2016·Nature Chemical Biology·Yuji OguraBenjamin F Cravatt
Jul 28, 2016·Nature Neuroscience·Richard M Ransohoff
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Mar 3, 2020·Frontiers in Neurology·Mikiei TanakaYumin Zhang
Dec 18, 2020·Frontiers in Neurology·Paola PerinCinzia Boselli
Jan 29, 2020·Cell Chemical Biology·Myungsun ShinKu-Lung Hsu
Jun 15, 2021·RSC Medicinal Chemistry·Tyler A ShawJohn Paul Pezacki
Oct 6, 2021·Proceedings of the National Academy of Sciences of the United States of America·Hui JingBenjamin F Cravatt

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Methods Mentioned

BETA
electrophoresis
RNA-seq
RNAseq
ELISA
transgenic
genotyping
Protein Assay
scraping

Software Mentioned

CIMminer
GraphPad Prism
ImageJ Analyzer
Image
ABPP
ProLuCID
Excel
DTASelect
ImageJ
Photoshop

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