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Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction

Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando Salinas, Lixin Sun, Justin Kung, Chengsong Xie, Braden Oldham, Mantosh Kumar, Sarah Hawes, Jinhui Ding, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Guohong Cui, Yulong Li, Huaibin Cai, Beisha Tang
doi: https://doi.org/10.1101/2021.12.09.471983
Zhenhua Liu
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Nannan Yang
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Jie Dong
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
3Clinical Research Center on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116011, China
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Wotu Tian
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
4Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 20025, China
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Lisa Chang
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Jinghong Ma
5Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
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Jifeng Guo
2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Jieqiong Tan
6Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
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Ao Dong
7State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
8PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
9Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
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Kaikai He
7State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
8PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
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Jingheng Zhou
10In Vivo Neurobiology Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Resat Cinar
11Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Junbing Wu
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Armando Salinas
12Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA
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Lixin Sun
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Justin Kung
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Chengsong Xie
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Braden Oldham
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Mantosh Kumar
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Sarah Hawes
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Jinhui Ding
13Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Lupeng Wang
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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Tao Wang
14Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
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Piu Chan
5Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing 100053, China
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Zhuohua Zhang
6Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
15Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
16Department of Neurosciences, University of South China Medical School, Hengyang, China
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Weidong Le
3Clinical Research Center on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, 116011, China
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Shengdi Chen
4Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 20025, China
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David M. Lovinger
12Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA
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Guohong Cui
10In Vivo Neurobiology Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, U.S.A.
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Yulong Li
7State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing 100871, China
8PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China
9Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China
17Chinese Institute for Brain Research, Beijing 102206, China
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Huaibin Cai
1Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, U.S.A.
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  • For correspondence: bstang7398@163.com caih@mail.nih.gov
Beisha Tang
2Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
6Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410008, China
18National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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  • For correspondence: bstang7398@163.com caih@mail.nih.gov
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Abstract

2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinson’s disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase α and β (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵^ Dr. Chengsong Xie died from stomach cancer in October 2020.

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Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction
Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando Salinas, Lixin Sun, Justin Kung, Chengsong Xie, Braden Oldham, Mantosh Kumar, Sarah Hawes, Jinhui Ding, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Guohong Cui, Yulong Li, Huaibin Cai, Beisha Tang
bioRxiv 2021.12.09.471983; doi: https://doi.org/10.1101/2021.12.09.471983
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Deficiency in endocannabinoid synthase DAGLB contributes to Parkinson’s disease and dopaminergic neuron dysfunction
Zhenhua Liu, Nannan Yang, Jie Dong, Wotu Tian, Lisa Chang, Jinghong Ma, Jifeng Guo, Jieqiong Tan, Ao Dong, Kaikai He, Jingheng Zhou, Resat Cinar, Junbing Wu, Armando Salinas, Lixin Sun, Justin Kung, Chengsong Xie, Braden Oldham, Mantosh Kumar, Sarah Hawes, Jinhui Ding, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Guohong Cui, Yulong Li, Huaibin Cai, Beisha Tang
bioRxiv 2021.12.09.471983; doi: https://doi.org/10.1101/2021.12.09.471983

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