Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

Nat Commun. 2022 Jun 17;13(1):3490. doi: 10.1038/s41467-022-31168-9.

Zhenhua Liu ^# ¹ ², Nannan Yang ^# ¹ ², Jie Dong ^# ¹ ³, Wotu Tian ¹ ⁴, Lisa Chang ¹, Jinghong Ma ⁵, Jifeng Guo ², Jieqiong Tan ⁶, Ao Dong ⁷ ⁸ ⁹, Kaikai He ⁷ ⁸, Jingheng Zhou ¹⁰, Resat Cinar ¹¹, Junbing Wu ¹, Armando G Salinas ¹², Lixin Sun ¹, Mantosh Kumar ¹, Breanna T Sullivan ¹, Braden B Oldham ¹, Vanessa Pitz ¹³, Mary B Makarious ¹³, Jinhui Ding ¹⁴, Justin Kung ¹, Chengsong Xie ¹, Sarah L Hawes ¹, Lupeng Wang ¹, Tao Wang ¹⁵, Piu Chan ⁵, Zhuohua Zhang ⁶ ¹⁶, Weidong Le ³ ¹⁷, Shengdi Chen ⁴, David M Lovinger ¹², Cornelis Blauwendraat ¹⁸, Andrew B Singleton ¹³ ¹⁹, Guohong Cui ¹⁰, Yulong Li ⁷ ⁸ ⁹ ²⁰, Huaibin Cai ²¹, Beisha Tang ²² ²³ ²⁴ ²⁵

Affiliations

1 Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
2 Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China.
3 Clinical Research Center on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, 116011, Dalian, Liaoning, China.
4 Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 20025, Shanghai, China.
5 Department of Neurology, Xuanwu Hospital of Capital Medical University, 100053, Beijing, China.
6 Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410008, Changsha, Hunan, China.
7 State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, 100871, Beijing, China.
8 PKU-IDG/McGovern Institute for Brain Research, 100871, Beijing, China.
9 Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China.
10 In Vivo Neurobiology Group, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, 27709, USA.
11 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
12 Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, 20852, USA.
13 Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
14 Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
15 Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, Hubei, China.
16 Department of Neurosciences, University of South China Medical School, 421200, Hengyang, Hunan, China.
17 Institute of Neurology, Sichuan Academy of Medical Sciences-Sichuan Provincial Hospital, Medical School of University of Electronics & Technology of China, 610045, Chengdu, Sichuan, China.
18 Integrative Neurogenomics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
19 Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, 20892, USA.
20 Chinese Institute for Brain Research, 102206, Beijing, China.
21 Transgenic Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. [email protected].
22 Department of Neurology, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. [email protected].
23 Centre for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, 410008, Changsha, Hunan, China. [email protected].
24 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, 410008, Changsha, Hunan, China. [email protected].
25 Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, 410008, Changsha, Hunan, China. [email protected].
# Contributed equally.

PMID: 35715418 DOI: 10.1038/s41467-022-31168-9

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.

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