New Targets for Parkinson's Disease: Adhesion G Protein-Coupled Receptor B1 is Downregulated by AMP-Activated Protein...

While progressive dopaminergic neurodegeneration is responsible for the cardinal motor defects in Parkinson's disease (PD), new diagnostics and therapeutic targets are necessary to effectively address this major global health burden. We evaluated whether the adhesion G protein-coupled receptor B1 (ADGRB1, formerly BAI1, brain-specific angiogenesis inhibitor 1) might contribute to dopaminergic neuronal loss. We used bioinformatic analyses, as well as in vitro and in vivo PD models. We report in this study that ADGRB1 is decreased in PD and that the ADGRB1 level is specifically decreased in dopaminergic neurons in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. In primary mouse mesencephalic neurons and human neuroblastoma cell lines, 1-methyl-4-phenylpyridinium (MPP⁺), a toxic metabolite of MPTP, suppressed the expression of ADGRB1. Moreover, we applied a network generation tool, Ingenuity Pathway Analysis^®, with the transcriptomics dataset to extend the upstream regulatory pathway of ADGRB1 expression. AMP-activated protein kinase (AMPK) was predicted as a regulator, and consequently, 5-aminoimidazole-4-carboxamide ribonucleotide, a specific activator of AMPK, reduced the ADGRB1 protein level. Finally, ADGRB1 overexpression decreased nuclear condensation induced by MPP⁺ treatment. Taken together, we observed that decreased ADGRB1 by activation of AMPK induced neuronal cell death in MPTP/MPP⁺-mediated PD models, suggesting that ADGRB1 might potentially play a survival role in the neurodegenerative pathway of PD. These data offer new insights into dopaminergic cell death with therapeutic implications for neurodegenerative disorders.