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

Author

Listed:
  • Zhenhua Liu

    (National Institute on Aging, National Institutes of Health
    Central South University)

  • Nannan Yang

    (National Institute on Aging, National Institutes of Health
    Central South University)

  • Jie Dong

    (National Institute on Aging, National Institutes of Health
    Dalian Medical University)

  • Wotu Tian

    (National Institute on Aging, National Institutes of Health
    Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine)

  • 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
    PKU-IDG/McGovern Institute for Brain Research
    Peking University)

  • Kaikai He

    (Peking University School of Life Sciences
    PKU-IDG/McGovern Institute for Brain Research)

  • 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
    University of South China Medical School)

  • Weidong Le

    (Dalian Medical University
    Medical School of University of Electronics & Technology of China)

  • 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
    National Institutes of Health)

  • Guohong Cui

    (National Institute of Environmental Health Sciences)

  • Yulong Li

    (Peking University School of Life Sciences
    PKU-IDG/McGovern Institute for Brain Research
    Peking University
    Chinese Institute for Brain Research)

  • Huaibin Cai

    (National Institute on Aging, National Institutes of Health)

  • Beisha Tang

    (Central South University
    Central South University
    Xiangya Hospital, Central South University
    Central South University)

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.

Suggested Citation

  • 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 Su, 2022. "Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31168-9
    DOI: 10.1038/s41467-022-31168-9
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