{"doi":"10.1101/2021.12.09.471983","title":"Deficiency in endocannabinoid synthase <i>DAGLB</i> contributes to Parkinson’s disease and dopaminergic neuron dysfunction","abstract":"Abstract 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":219761,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9548,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":818993,"name":"Nannan Yang","orcid":"0000-0002-3003-9702","position":1,"is_corresponding":false},{"id":397723,"name":"Jie Dong","orcid":"0000-0002-8148-3838","position":2,"is_corresponding":false},{"id":461658,"name":"Wotu Tian","orcid":"0000-0002-1235-9817","position":3,"is_corresponding":false},{"id":461661,"name":"Lisa Chang","orcid":"0009-0008-8879-9246","position":4,"is_corresponding":false},{"id":346894,"name":"Jinghong Ma","orcid":"0000-0002-3458-1363","position":5,"is_corresponding":false},{"id":818994,"name":"Jifeng Guo","orcid":"0000-0002-3658-3928","position":6,"is_corresponding":false},{"id":404080,"name":"Jieqiong Tan","orcid":"0000-0003-0730-1095","position":7,"is_corresponding":false},{"id":571610,"name":"Ao Dong","orcid":"0000-0002-2821-9528","position":8,"is_corresponding":false},{"id":571611,"name":"Kaikai He","orcid":"0000-0003-2002-4862","position":9,"is_corresponding":false},{"id":226414,"name":"Jingheng Zhou","orcid":"0000-0003-0280-6166","position":10,"is_corresponding":false},{"id":260243,"name":"Reşat Çınar","orcid":"0000-0002-8597-7253","position":11,"is_corresponding":false},{"id":637672,"name":"Junbing Wu","orcid":null,"position":12,"is_corresponding":false},{"id":662401,"name":"Armando G. 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