Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.
Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.
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内源性大麻素合成酶DAGLB的缺乏导致早发性帕金森综合征和鼠黑质多巴胺能神经元功能障碍。
DOI：
10.1038/s41467-022-31168-9
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发表时间：
2022-06-17
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
内源性大麻素（Endocannabinoid，eCB），2-花生四烯酰甘油（2-arachidonoyl-glycerol，2-AG），是大脑中含量最丰富的内源性大麻素，调节多种神经功能。在此，我们将2-AG合酶二酰甘油脂肪酶β（DAGLB）中的多个纯合功能丧失突变与早发性常染色体隐性帕金森综合征联系起来。DAGLB是人和小鼠黑质多巴胺能神经元中主要的2-AG合酶。在小鼠中，SN 2-AG水平与运动技能获得过程中的运动表现显著相关.黑质DAN中Daglb的基因敲除大大降低了SN 2-AG水平，并损害了运动技能学习，特别是跨会话学习。相反，药理学抑制2-AG降解增加黑质2-AG水平，DAN活性和多巴胺释放和拯救运动技能学习缺陷。总之，我们证明DAGLB缺乏有助于帕金森病的发病机制，揭示DAGLB介导的2-AG生物合成在黑质DAN中调节神经元活性和多巴胺释放的重要性，并表明2-AG增强在缓解帕金森病中的潜在益处。2-花生四烯酰甘油（2-AG）是大脑中丰富的内源性大麻素，调节多种神经功能。在这里，作者从6名早发性帕金森综合征患者中鉴定出4种双甘油脂酶β（DAGLB）功能缺失突变。在小鼠中，多巴胺神经元中DAGLB的丧失降低了神经元活性并损害了运动功能，而2-AG水平的增加促进了神经元活性并挽救了运动缺陷。
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. 2- arachidonoylglycerol (2-AG), an abundant endocannabinoid in the brain, regulates diverse neural functions. Here, the authors identified four loss-of-function mutations in dicylglycerol lipase β (DAGLB) from six patients with early onset Parkinsonism. In mice, loss of DAGLB in dopamine neurons reduced neuronal activity and impaired locomotor function and augmentation of 2-AG levels boosted neuronal activity and rescued locomotor deficits.
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影响因子：
11.2
作者：
Beeler, Jeff A.;Cao, Zhen Fang Huang;Kheirbek, Mazen A.;Ding, Yunmin;Koranda, Jessica;Murakami, Mari;Kang, Un Jung;Zhuang, Xiaoxi
通讯作者：
Zhuang, Xiaoxi
影响因子：
3.7
作者：
Davis MI;Crittenden JR;Feng AY;Kupferschmidt DA;Naydenov A;Stella N;Graybiel AM;Lovinger DM
通讯作者：
Lovinger DM
基底神经节抑制输入对黑质多巴胺能神经元的功能剖析。
影响因子：
8.8
作者：
Evans, Rebekah C.;Twedell, Emily L.;Zhu, Manhua;Ascencio, Jefferson;Zhang, Renshu;Khaliq, Zayd M.
通讯作者：
Khaliq, Zayd M.
影响因子：
3.5
作者：
Carmichael K;Evans RC;Lopez E;Sun L;Kumar M;Ding J;Khaliq ZM;Cai H
通讯作者：
Cai H
影响因子：
1.7
作者：
French, ED;Dillon, K;Wu, XF
通讯作者：
Wu, XF