PT  - JOURNAL ARTICLE
AU  - Zhenhua Liu
AU  - Nannan Yang
AU  - Jie Dong
AU  - Wotu Tian
AU  - Lisa Chang
AU  - Jinghong Ma
AU  - Jifeng Guo
AU  - Jieqiong Tan
AU  - Ao Dong
AU  - Kaikai He
AU  - Jingheng Zhou
AU  - Resat Cinar
AU  - Junbing Wu
AU  - Armando Salinas
AU  - Lixin Sun
AU  - Justin Kung
AU  - Chengsong Xie
AU  - Braden Oldham
AU  - Mantosh Kumar
AU  - Sarah Hawes
AU  - Jinhui Ding
AU  - Lupeng Wang
AU  - Tao Wang
AU  - Piu Chan
AU  - Zhuohua Zhang
AU  - Weidong Le
AU  - Shengdi Chen
AU  - David M. Lovinger
AU  - Guohong Cui
AU  - Yulong Li
AU  - Huaibin Cai
AU  - Beisha Tang
TI  - Deficiency in endocannabinoid synthase <em>DAGLB</em> contributes to Parkinson’s disease and dopaminergic neuron dysfunction
AID  - 10.1101/2021.12.09.471983
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.09.471983
4099  - http://biorxiv.org/content/early/2021/12/09/2021.12.09.471983.short
4100  - http://biorxiv.org/content/early/2021/12/09/2021.12.09.471983.full
AB  - 2-arachidonoyl-glycerol (2-AG), the most abundant endocannabinoid (eCB) in the brain, regulates diverse neural functions. However, whether 2-AG deficiency contributes to Parkinson’s disease (PD) and nigral dopaminergic neurons (DANs) dysfunction is unclear. Diacylglycerol lipase α and β (DAGLA and DAGLB) mediate the biosynthesis of 2-AG. Using homozygosity mapping and whole-exome sequencing, we linked multiple homozygous loss-of-function mutations in DAGLB to a form of early-onset autosomal recessive PD. We then used RNA sequencing and fiber photometry with genetically encoded eCB sensors to demonstrate that DAGLB is the main 2-AG synthase in nigral DANs. Genetic knockdown of Daglb by CRISPR/Cas9 in mouse nigral DANs substantially reduces 2-AG levels in the substantia nigra (SN). The SN 2-AG levels are markedly correlated with the vigor of movement during the acquisition of motor skills, while Daglb-deficiency impairs motor learning. Conversely, pharmacological enhancement of 2-AG levels increases nigral DAN activity and dopamine release and improves motor learning. Together, we demonstrate that DAGLB-deficiency contributes to the etiopathogenesis of PD, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neural activity and dopamine release, and provide preclinical evidence for the beneficial effects of 2-AG augmentation in PD treatment.Competing Interest StatementThe authors have declared no competing interest.