Recently, Professor Tang Beisha’s team from Xiangya Hospital of Central South University and Professor Huaibin Cai from U.S. National Institutes of Health jointly published an article titled “Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction” online in Nature Communications (IF=14.919), identifying a novel pathogenic gene of Parkinson’s disease (PD) or Parkinsonism, diacylglycerol lipase β (DAGLB), and revealing the role of endocannabinoid (eCB) in the etiopathogenesis of PD. Professor Tang Beisha, Xiangya Hospital of Central South University and Professor Huaibin Cai, US National Institutes of Health(NIH) are the co-corresponding authors of the article. Dr. Liu Zhenhua and Ph.D. student Yang Nannan from Xiangya Hospital of Central South University, as well as Dr. Jie Dong from the U.S. National Institutes of Health are the co-first authors.
The study applied homozygosity mapping(HEC) and NGS technology to carry out genetic analysis on a group of affected PD families, and finally screened out the candidate gene -- DAGLB, and verified in early onset autosomal recessive Parkinsonism, these pathogenic mutations can disrupt the stability and dysfunction of DAGLB protein.
DAGLB is a endocannabinoid 2-AG synthase, and its homolog is DAGLA. In order to elucidate the pathogenic mechanism of DAGLB mutations in PD, RNAscope and single-cell RNA sequencing were firstly performed to comparatively analyze the levels of DAGLB and its homolog DAGLA in substantia nigra(SN) dopaminergic neurons (DAN) of human brain and mouse brain respectively, and it was found that the DAGLB protein was specifically highly expressed in the nigral DAN of human and mouse brain. Using a fiber photometry recording combined with an eCB sensor, eCB signals in the DAN of free-moving wild-type mice and DAN- Daglb knockdown(KD) mice revealed that Daglb is the predominant eCB synthase in DAN. Subsequently, combined with fiber photometry recording in vivo imaging and behavioral analysis of mice, it was found that the eCB synthesized by Daglb are closely related to rotarod locomotor skill learning in mice, DAN-Daglb KD mice showed markedly impairments in the rotarod locomotor skill learning, and confirmed that knockdown of Daglb in DAN can suppress the nigral DAN activity and the release of dopamine neurotransmitter by reducing 2-AG biosynthesis. Finally, the 2-AG degradation inhibitor JZL184 treatment could restore of 2-AG level in DAN-Daglb KD mice, so as to rescue the phenotype of rotarod locomotor skill learning impairment in DAN-Daglb KD mice.
This study not only found and identified a new pathogenic gene for PD -- DAGLB, but also clarified the important role of eCB in Parkinson's disease, which is expected to provide an important theoretical basis for clinical treatment. This study is strongly supported by Professor Li Yulong form Peking University, Professor Chen Biao from Xuanwu Hospital of Capital Medical University, Professor Guohong Cui from U.S. NIH/NIEHS, Professor David Lovinger from U.S. NIH/NIAAA, and Professor Andrew Singleton from U.S. NIH/NIA, etc.
Professor Tang Beisha’s team has been dedicated to studies on neurodegenerative diseases and genetic diseases. In recent years, the team has innovatively brought forth the "LEC" and "HEC" gene cloning strategies and identified and cloned SCA35 pathogenic gene TGM6, ARCA pathogenic genes CHIP and UBA5, CMT pathogenic gene HSP22, PKD pathogenic gene PRRT2, FCMTE pathogenic gene SAMD12 and so on. Moreover, the team has systematically developed high-throughput sequencing technology and established a molecular genetic diagnosis and sub-typing platform for neurodegenerative and neurogenetic diseases. Currently, the team of Prof. Tang Beisha focuses on clinical cohort studies, genomics studies, screening and identification of new pathogenic genes/novel susceptibility genes associated with Parkinson's disease (PD). The team has established the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) (http://pd--mdcnc-com) to identify new PD causal genes-DAGLB and NUS1, proposed "Digenic Inheritance in PD", "PLA2G6 new variant - new phenotype (AREP)"and "PD risk gene SNPs interaction pattern and cumulative effect pattern ", and also established the PD genomics analysis platform-Gene4PD（http://www.genemed.tech/gene4pd/home ).
Link to the Article: https://www.nature.com/articles/s41467-022-31168-9
Xiangya Hospital Central South University
All Rights Reserved