Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction
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Published:2022-06-17
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Liu Zhenhua, Yang Nannan, Dong Jie, Tian Wotu, Chang Lisa, Ma Jinghong, Guo JifengORCID, Tan Jieqiong, Dong AoORCID, He KaikaiORCID, Zhou JinghengORCID, Cinar ResatORCID, Wu Junbing, Salinas Armando G.ORCID, Sun Lixin, Kumar Mantosh, Sullivan Breanna T., Oldham Braden B.ORCID, Pitz VanessaORCID, Makarious Mary B.ORCID, Ding Jinhui, Kung Justin, Xie Chengsong, Hawes Sarah L., Wang Lupeng, Wang Tao, Chan Piu, Zhang Zhuohua, Le Weidong, Chen Shengdi, Lovinger David M., Blauwendraat CornelisORCID, Singleton Andrew B., Cui GuohongORCID, Li YulongORCID, Cai HuaibinORCID, Tang BeishaORCID
Abstract
AbstractEndocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase β (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.
Funder
U.S. Department of Health & Human Services | NIH | National Institute on Aging
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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