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Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction
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 t...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205912/ https://www.ncbi.nlm.nih.gov/pubmed/35715418 http://dx.doi.org/10.1038/s41467-022-31168-9 |
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author | Liu, Zhenhua Yang, Nannan Dong, Jie Tian, Wotu Chang, Lisa Ma, Jinghong Guo, Jifeng Tan, Jieqiong Dong, Ao He, Kaikai Zhou, Jingheng Cinar, Resat Wu, Junbing Salinas, Armando G. Sun, Lixin Kumar, Mantosh Sullivan, Breanna T. Oldham, Braden B. Pitz, Vanessa Makarious, Mary B. Ding, Jinhui Kung, Justin Xie, Chengsong Hawes, Sarah L. Wang, Lupeng Wang, Tao Chan, Piu Zhang, Zhuohua Le, Weidong Chen, Shengdi Lovinger, David M. Blauwendraat, Cornelis Singleton, Andrew B. Cui, Guohong Li, Yulong Cai, Huaibin Tang, Beisha |
author_facet | Liu, Zhenhua Yang, Nannan Dong, Jie Tian, Wotu Chang, Lisa Ma, Jinghong Guo, Jifeng Tan, Jieqiong Dong, Ao He, Kaikai Zhou, Jingheng Cinar, Resat Wu, Junbing Salinas, Armando G. Sun, Lixin Kumar, Mantosh Sullivan, Breanna T. Oldham, Braden B. Pitz, Vanessa Makarious, Mary B. Ding, Jinhui Kung, Justin Xie, Chengsong Hawes, Sarah L. Wang, Lupeng Wang, Tao Chan, Piu Zhang, Zhuohua Le, Weidong Chen, Shengdi Lovinger, David M. Blauwendraat, Cornelis Singleton, Andrew B. Cui, Guohong Li, Yulong Cai, Huaibin Tang, Beisha |
author_sort | Liu, Zhenhua |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9205912 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92059122022-06-19 Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction Liu, Zhenhua Yang, Nannan Dong, Jie Tian, Wotu Chang, Lisa Ma, Jinghong Guo, Jifeng Tan, Jieqiong Dong, Ao He, Kaikai Zhou, Jingheng Cinar, Resat Wu, Junbing Salinas, Armando G. Sun, Lixin Kumar, Mantosh Sullivan, Breanna T. Oldham, Braden B. Pitz, Vanessa Makarious, Mary B. Ding, Jinhui Kung, Justin Xie, Chengsong Hawes, Sarah L. Wang, Lupeng Wang, Tao Chan, Piu Zhang, Zhuohua Le, Weidong Chen, Shengdi Lovinger, David M. Blauwendraat, Cornelis Singleton, Andrew B. Cui, Guohong Li, Yulong Cai, Huaibin Tang, Beisha Nat Commun Article 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. Nature Publishing Group UK 2022-06-17 /pmc/articles/PMC9205912/ /pubmed/35715418 http://dx.doi.org/10.1038/s41467-022-31168-9 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Liu, Zhenhua Yang, Nannan Dong, Jie Tian, Wotu Chang, Lisa Ma, Jinghong Guo, Jifeng Tan, Jieqiong Dong, Ao He, Kaikai Zhou, Jingheng Cinar, Resat Wu, Junbing Salinas, Armando G. Sun, Lixin Kumar, Mantosh Sullivan, Breanna T. Oldham, Braden B. Pitz, Vanessa Makarious, Mary B. Ding, Jinhui Kung, Justin Xie, Chengsong Hawes, Sarah L. Wang, Lupeng Wang, Tao Chan, Piu Zhang, Zhuohua Le, Weidong Chen, Shengdi Lovinger, David M. Blauwendraat, Cornelis Singleton, Andrew B. Cui, Guohong Li, Yulong Cai, Huaibin Tang, Beisha Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title | Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title_full | Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title_fullStr | Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title_full_unstemmed | Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title_short | Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction |
title_sort | deficiency in endocannabinoid synthase daglb contributes to early onset parkinsonism and murine nigral dopaminergic neuron dysfunction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205912/ https://www.ncbi.nlm.nih.gov/pubmed/35715418 http://dx.doi.org/10.1038/s41467-022-31168-9 |
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