Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral 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 G. Salinas, Lixin Sun, Mantosh Kumar, Breanna T. Sullivan, Braden B. Oldham, Vanessa Pitz, Mary B. Makarious, Jinhui Ding, Justin Kung, Chengsong Xie, Sarah L. Hawes, Lupeng Wang, Tao Wang, Piu Chan, Zhuohua Zhang, Weidong Le, Shengdi Chen, David M. Lovinger, Cornelis Blauwendraat, Andrew B. Singleton, Guohong Cui, Yulong Li, Huaibin Cai () and Beisha Tang ()
Additional contact information
Zhenhua Liu: National Institute on Aging, National Institutes of Health
Nannan Yang: National Institute on Aging, National Institutes of Health
Jie Dong: National Institute on Aging, National Institutes of Health
Wotu Tian: National Institute on Aging, National Institutes of Health
Lisa Chang: National Institute on Aging, National Institutes of Health
Jinghong Ma: Xuanwu Hospital of Capital Medical University
Jifeng Guo: Central South University
Jieqiong Tan: Central South University
Ao Dong: Peking University School of Life Sciences
Kaikai He: Peking University School of Life Sciences
Jingheng Zhou: National Institute of Environmental Health Sciences
Resat Cinar: National Institutes of Health
Junbing Wu: National Institute on Aging, National Institutes of Health
Armando G. Salinas: National Institutes of Health
Lixin Sun: National Institute on Aging, National Institutes of Health
Mantosh Kumar: National Institute on Aging, National Institutes of Health
Breanna T. Sullivan: National Institute on Aging, National Institutes of Health
Braden B. Oldham: National Institute on Aging, National Institutes of Health
Vanessa Pitz: National Institutes of Health
Mary B. Makarious: National Institutes of Health
Jinhui Ding: National Institute on Aging, National Institutes of Health
Justin Kung: National Institute on Aging, National Institutes of Health
Chengsong Xie: National Institute on Aging, National Institutes of Health
Sarah L. Hawes: National Institute on Aging, National Institutes of Health
Lupeng Wang: National Institute on Aging, National Institutes of Health
Tao Wang: Huazhong University of Science and Technology
Piu Chan: Xuanwu Hospital of Capital Medical University
Zhuohua Zhang: Central South University
Weidong Le: Dalian Medical University
Shengdi Chen: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
David M. Lovinger: National Institutes of Health
Cornelis Blauwendraat: National Institute on Aging, National Institutes of Health
Andrew B. Singleton: National Institutes of Health
Guohong Cui: National Institute of Environmental Health Sciences
Yulong Li: Peking University School of Life Sciences
Huaibin Cai: National Institute on Aging, National Institutes of Health
Beisha Tang: Central South University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31168-9

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