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; Beisha Tang

doi:10.1038/s41467-022-31168-9

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. MakariousJinhui 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, Beisha Tang

Houston Methodist

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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.

Original language	English (US)
Article number	3490
Pages (from-to)	3490
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31168-9
State	Published - Jun 17 2022

Keywords

Animals
Dopamine/metabolism
Dopaminergic Neurons/metabolism
Endocannabinoids/metabolism
Lipoprotein Lipase/metabolism
Mice
Parkinsonian Disorders/metabolism
Substantia Nigra/metabolism

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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10.1038/s41467-022-31168-9

Cite this

Liu, Z., Yang, N., Dong, J., Tian, W., Chang, L., Ma, J., Guo, J., Tan, J., Dong, A., He, K., Zhou, J., Cinar, R., Wu, J., Salinas, A. G., Sun, L., Kumar, M., Sullivan, B. T., Oldham, B. B., Pitz, V., ... Tang, B. (2022). Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction. Nature Communications, 13(1), 3490. Article 3490. https://doi.org/10.1038/s41467-022-31168-9

Liu, Z, Yang, N, Dong, J, Tian, W, Chang, L, Ma, J, Guo, J, Tan, J, Dong, A, He, K, Zhou, J, Cinar, R, Wu, J, Salinas, AG, Sun, L, Kumar, M, Sullivan, BT, Oldham, BB, Pitz, V, Makarious, MB, Ding, J, Kung, J, Xie, C, Hawes, SL, Wang, L, Wang, T, Chan, P, Zhang, Z, Le, W, Chen, S, Lovinger, DM, Blauwendraat, C, Singleton, AB, Cui, G, Li, Y, Cai, H & Tang, B 2022, 'Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction', Nature Communications, vol. 13, no. 1, 3490, pp. 3490. https://doi.org/10.1038/s41467-022-31168-9

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

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.",

keywords = "Animals, Dopamine/metabolism, Dopaminergic Neurons/metabolism, Endocannabinoids/metabolism, Lipoprotein Lipase/metabolism, Mice, Parkinsonian Disorders/metabolism, Substantia Nigra/metabolism",

author = "Zhenhua Liu and Nannan Yang and Jie Dong and Wotu Tian and Lisa Chang and Jinghong Ma and Jifeng Guo and Jieqiong Tan and Ao Dong and Kaikai He and Jingheng Zhou and Resat Cinar and Junbing Wu and Salinas, {Armando G.} and Lixin Sun and Mantosh Kumar and Sullivan, {Breanna T.} and Oldham, {Braden B.} and Vanessa Pitz and Makarious, {Mary B.} and Jinhui Ding and Justin Kung and Chengsong Xie and Hawes, {Sarah L.} and Lupeng Wang and Tao Wang and Piu Chan and Zhuohua Zhang and Weidong Le and Shengdi Chen and Lovinger, {David M.} and Cornelis Blauwendraat and Singleton, {Andrew B.} and Guohong Cui and Yulong Li and Huaibin Cai and Beisha Tang",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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doi = "10.1038/s41467-022-31168-9",

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T1 - Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction

AU - Liu, Zhenhua

AU - Yang, Nannan

AU - Dong, Jie

AU - Tian, Wotu

AU - Chang, Lisa

AU - Ma, Jinghong

AU - Guo, Jifeng

AU - Tan, Jieqiong

AU - Dong, Ao

AU - He, Kaikai

AU - Zhou, Jingheng

AU - Cinar, Resat

AU - Wu, Junbing

AU - Salinas, Armando G.

AU - Sun, Lixin

AU - Kumar, Mantosh

AU - Sullivan, Breanna T.

AU - Oldham, Braden B.

AU - Pitz, Vanessa

AU - Makarious, Mary B.

AU - Ding, Jinhui

AU - Kung, Justin

AU - Xie, Chengsong

AU - Hawes, Sarah L.

AU - Wang, Lupeng

AU - Wang, Tao

AU - Chan, Piu

AU - Zhang, Zhuohua

AU - Le, Weidong

AU - Chen, Shengdi

AU - Lovinger, David M.

AU - Blauwendraat, Cornelis

AU - Singleton, Andrew B.

AU - Cui, Guohong

AU - Li, Yulong

AU - Cai, Huaibin

AU - Tang, Beisha

PY - 2022/6/17

Y1 - 2022/6/17

N2 - 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.

AB - 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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KW - Mice

KW - Parkinsonian Disorders/metabolism

KW - Substantia Nigra/metabolism

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ER -

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

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