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

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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
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31168-9
State	Published - Dec 2022

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-31168-9

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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]. 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. https://doi.org/10.1038/s41467-022-31168-9

@article{6194b276e3b7464f9edc6379adfb2e81,

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.",

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 = "Funding Information: This work is supported in part by the National Key Plan for Scientific Research and Development of China grants (BT, Grant No. 2016YFC1306000), the National Natural Science Foundation of China (BT, Grant No. 81430023), and the Intramural Research Programs of National Institute on Aging, NIH (HC, ZIA AG000944, AG000928), National Institute of Alcoholism and Alcohol Abuse (DML, ZIA AA000416; AS, K99/R00 AA025991), and National Institute of Environmental Health Sciences (GC, ZIA ES103310). We are indebted to the participation of the patients and their family members in this study. We thank Accelerating Medicine Partnership- Parkinson{\textquoteright}s Disease (AMP-PD, https://www.amp-pd.org) Knowledge Platform for allowing us to use the datasets from European decent. More detailed AMP-PD and AMP-PD Cohort acknowledgements are included in the supporting information. We thank NIMH rodent behavioral core for assisting in behavioral tests, Dr. Josephine M. Egan of NIA for providing the Cnr1loxP/loxPmice, Dr. Ku-Lung Hsu from University of Virginia for providing the Daglb germline KO mice, and members of Cai lab for their suggestions and technical assistance. Drs. Zhenhua Liu and Nannan Yang were participants in the NIH Graduate Partnership Program and graduate students at Central South University. Dr. Wotu Tian was a participant in the NIH Graduate Partnership Program and a graduate student at Shanghai Jiao Tong University School of Medicine. Dr. Jie Dong was a participant in the NIH Graduate Partnership Program and a graduate student at Dalian Medical University. Funding Information: This work is supported in part by the National Key Plan for Scientific Research and Development of China grants (BT, Grant No. 2016YFC1306000), the National Natural Science Foundation of China (BT, Grant No. 81430023), and the Intramural Research Programs of National Institute on Aging, NIH (HC, ZIA AG000944, AG000928), National Institute of Alcoholism and Alcohol Abuse (DML, ZIA AA000416; AS, K99/R00 AA025991), and National Institute of Environmental Health Sciences (GC, ZIA ES103310). We are indebted to the participation of the patients and their family members in this study. We thank Accelerating Medicine Partnership- Parkinson{\textquoteright}s Disease (AMP-PD, https://www.amp-pd.org ) Knowledge Platform for allowing us to use the datasets from European decent. More detailed AMP-PD and AMP-PD Cohort acknowledgements are included in the supporting information. We thank NIMH rodent behavioral core for assisting in behavioral tests, Dr. Josephine M. Egan of NIA for providing the Cnr1 mice, Dr. Ku-Lung Hsu from University of Virginia for providing the Daglb germline KO mice, and members of Cai lab for their suggestions and technical assistance. Drs. Zhenhua Liu and Nannan Yang were participants in the NIH Graduate Partnership Program and graduate students at Central South University. Dr. Wotu Tian was a participant in the NIH Graduate Partnership Program and a graduate student at Shanghai Jiao Tong University School of Medicine. Dr. Jie Dong was a participant in the NIH Graduate Partnership Program and a graduate student at Dalian Medical University. loxP/loxP Funding Information: Open Access funding provided by the National Institutes of Health (NIH). Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

month = dec,

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

language = "English (US)",

volume = "13",

journal = "Nat Commun",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

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

N1 - Funding Information: This work is supported in part by the National Key Plan for Scientific Research and Development of China grants (BT, Grant No. 2016YFC1306000), the National Natural Science Foundation of China (BT, Grant No. 81430023), and the Intramural Research Programs of National Institute on Aging, NIH (HC, ZIA AG000944, AG000928), National Institute of Alcoholism and Alcohol Abuse (DML, ZIA AA000416; AS, K99/R00 AA025991), and National Institute of Environmental Health Sciences (GC, ZIA ES103310). We are indebted to the participation of the patients and their family members in this study. We thank Accelerating Medicine Partnership- Parkinson’s Disease (AMP-PD, https://www.amp-pd.org) Knowledge Platform for allowing us to use the datasets from European decent. More detailed AMP-PD and AMP-PD Cohort acknowledgements are included in the supporting information. We thank NIMH rodent behavioral core for assisting in behavioral tests, Dr. Josephine M. Egan of NIA for providing the Cnr1loxP/loxPmice, Dr. Ku-Lung Hsu from University of Virginia for providing the Daglb germline KO mice, and members of Cai lab for their suggestions and technical assistance. Drs. Zhenhua Liu and Nannan Yang were participants in the NIH Graduate Partnership Program and graduate students at Central South University. Dr. Wotu Tian was a participant in the NIH Graduate Partnership Program and a graduate student at Shanghai Jiao Tong University School of Medicine. Dr. Jie Dong was a participant in the NIH Graduate Partnership Program and a graduate student at Dalian Medical University. Funding Information: This work is supported in part by the National Key Plan for Scientific Research and Development of China grants (BT, Grant No. 2016YFC1306000), the National Natural Science Foundation of China (BT, Grant No. 81430023), and the Intramural Research Programs of National Institute on Aging, NIH (HC, ZIA AG000944, AG000928), National Institute of Alcoholism and Alcohol Abuse (DML, ZIA AA000416; AS, K99/R00 AA025991), and National Institute of Environmental Health Sciences (GC, ZIA ES103310). We are indebted to the participation of the patients and their family members in this study. We thank Accelerating Medicine Partnership- Parkinson’s Disease (AMP-PD, https://www.amp-pd.org ) Knowledge Platform for allowing us to use the datasets from European decent. More detailed AMP-PD and AMP-PD Cohort acknowledgements are included in the supporting information. We thank NIMH rodent behavioral core for assisting in behavioral tests, Dr. Josephine M. Egan of NIA for providing the Cnr1 mice, Dr. Ku-Lung Hsu from University of Virginia for providing the Daglb germline KO mice, and members of Cai lab for their suggestions and technical assistance. Drs. Zhenhua Liu and Nannan Yang were participants in the NIH Graduate Partnership Program and graduate students at Central South University. Dr. Wotu Tian was a participant in the NIH Graduate Partnership Program and a graduate student at Shanghai Jiao Tong University School of Medicine. Dr. Jie Dong was a participant in the NIH Graduate Partnership Program and a graduate student at Dalian Medical University. loxP/loxP Funding Information: Open Access funding provided by the National Institutes of Health (NIH). Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

PY - 2022/12

Y1 - 2022/12

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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U2 - 10.1038/s41467-022-31168-9

DO - 10.1038/s41467-022-31168-9

M3 - Article

C2 - 35715418

AN - SCOPUS:85132346006

VL - 13

JO - Nat Commun

JF - Nat Commun

SN - 2041-1723

IS - 1

M1 - 3490

ER -

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

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