ArticleNature communications2022
Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.
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38 citing papers in PubMed, 64 citations in OpenAlex.
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- Identification of DAGLB variants in Japanese early-onset Parkinson's disease.Journal of neural transmission (Vienna, Austria : 1996) · 2025Article
- Endocannabinoids disinhibit the ventral tegmental nucleus of Gudden to dorsal premammillary nucleus pathway to enhance escape behavior following learned threat experience.Nature communications · 2025Article
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- Molecularly distinct striatonigral neuron subtypes differentially regulate locomotion.Nature communications · 2025Article
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- Building an action circuit with nigrostriatal dopaminergic neurons and striatonigral neurons.Handbook of behavioral neuroscience · 2025Article
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- Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.Journal of neuroinflammation · 2024Article
- Metabolomic and Lipidomic Analysis of Manganese-Associated Parkinsonism: a Case-Control Study in Brescia, Italy.medRxiv : the preprint server for health sciences · 2024Article
- Calbindin and Girk2/Aldh1a1 define resilient vs vulnerable dopaminergic neurons in a primate Parkinson's disease model.NPJ Parkinson's disease · 2024Article
- From Classical to Alternative Pathways of 2-Arachidonoylglycerol Synthesis: AlterAGs at the Crossroad of Endocannabinoid and Lysophospholipid Signaling.Molecules (Basel, Switzerland) · 2024Review
- P2XBritish journal of pharmacology · 2024Article
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Authors and funding
37 authors at 8 institutions in 2 countries.
Zhenhua Liu *Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Nannan Yang *Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Jie Dong *Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Wotu TianTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Lisa ChangTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Jinghong MaDepartment of Neurology, Xuanwu Hospital of Capital Medical University, 100053, Beijing, China.
Jifeng GuoDepartment of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.ORCID 0000-0002-3658-3928
Jieqiong TanCentre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410008, Changsha, Hunan, China.
Ao DongState Key Laboratory of Membrane Biology, Peking University School of Life Sciences, 100871, Beijing, China.ORCID 0000-0002-2821-9528
Kaikai HeState Key Laboratory of Membrane Biology, Peking University School of Life Sciences, 100871, Beijing, China.ORCID 0000-0003-2002-4862
Jingheng ZhouIn Vivo Neurobiology Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA.ORCID 0000-0003-0280-6166
Resat CinarLaboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.ORCID 0000-0002-8597-7253
Junbing WuTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Armando G SalinasLaboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.ORCID 0000-0002-1682-128X
Lixin SunTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Mantosh KumarTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Breanna T SullivanTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Braden B OldhamTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.ORCID 0000-0002-4249-5502
Vanessa PitzMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.ORCID 0000-0002-2964-5553
Mary B MakariousMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.ORCID 0000-0002-7978-1051
Jinhui DingComputational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Justin KungTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Chengsong XieTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Sarah L HawesTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Lupeng WangTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Tao WangDepartment of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, Hubei, China.
Piu ChanDepartment of Neurology, Xuanwu Hospital of Capital Medical University, 100053, Beijing, China.
Zhuohua ZhangCentre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410008, Changsha, Hunan, China.
Weidong LeClinical Research Center on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, 116011, Dalian, Liaoning, China.
Shengdi ChenDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 20025, Shanghai, China.
David M LovingerLaboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.
Cornelis BlauwendraatIntegrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.ORCID 0000-0001-9358-8111
Andrew B SingletonMolecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Guohong CuiIn Vivo Neurobiology Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA.ORCID 0000-0002-4555-028X
Yulong LiState Key Laboratory of Membrane Biology, Peking University School of Life Sciences, 100871, Beijing, China.ORCID 0000-0002-9166-9919
Huaibin CaiTransgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. caih@mail.nih.gov.ORCID 0000-0002-8596-6108
Beisha TangDepartment of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. bstang7398@163.com.ORCID 0000-0003-2120-1576
National Institutes of Health · USCentral South University · CNPeking University · CNCapital Medical University · CNNational Institute of Environmental Health Sciences · USDalian Medical University · CNShanghai Jiao Tong University · CNUnion Hospital · CN
Funding
Corticostriatal mechanisms of action learning and habit formationZIAAA000416 · NIAAA · NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM · PI LOVINGER, DAVID M · 2009 to 2025
$25.2MBasal Ganglia in Health and DiseaseZIAES103310 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI CUI, GUOHONG · 2016 to 2025
$23.6MMolecular and Pathophysiological Study of Parkinson's DiseaseZIAAG000928 · NIA · NATIONAL INSTITUTE ON AGING · PI CAI, HUAIBIN · 2011 to 2025
$15.8MThe Function and Pathogenic Mechanisms of LRRK2/Dardarin in Parkinson's DiseaseZIAAG000944 · NIA · NATIONAL INSTITUTE ON AGING · PI CAI, HUAIBIN · 2009 to 2025
$10.2MFunctions and Pathogenic Mechanisms of DAGLB and the Endocannabinoid System in Parkinson's DiseaseZIAAG000929 · NIA · NATIONAL INSTITUTE ON AGING · PI CAI, HUAIBIN · 2011 to 2025
$5.5MPathophysiological Study of Dopamine in Alzheimer's Disease and Related DemantiaZIAAG000540 · NIA · NATIONAL INSTITUTE ON AGING · PI CAI, HUAIBIN · 2020 to 2025
$2.8MChronic ethanol effects on cholinergic interneurons of the striatumR00AA025991 · NIAAA · LOUISIANA STATE UNIV HSC SHREVEPORT · PI SALINAS, ARMANDO · 2022 to 2024
$747kThe Function and Pathogenic Mechanisms of LRRK2/Dardarin in Parkinson's DiseaseZ01AG000944 · NIA · NATIONAL INSTITUTE ON AGING · PI CAI, HUAIBIN · 2008 to 2008
$499kChronic ethanol effects on cholinergic interneurons of the striatumK99AA025991 · NIAAA · GEORGE MASON UNIVERSITY · PI SALINAS, ARMANDO · 2018 to 2020
$287kIntramural NIH HHS Z01 AG000944Intramural NIH HHS ZIA AA000416Intramural NIH HHS ZIA AG000944Intramural NIH HHS ZIA ES103310NIAAA NIH HHS K99 AA025991NIAAA NIH HHS R00 AA025991
Abstract
Endocannabinoid (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.
Indexed as
Dopaminergic NeuronsParkinsonian DisordersAnimalsDopamineEndocannabinoidsLipoprotein LipaseMiceSubstantia Nigradiacylglycerol lipase beta, mouseDopamineEndocannabinoidsLipoprotein Lipase
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