β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease

Copy number mutations implicate excess production of a-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the beta 2-adrenoreceptor (beta 2AR) is a regulator of the a-synuclein gene (SNCA). beta 2AR ligands modulate SNCA transcription through histone 3 lysine 27 acetylation of its promoter and enhancers. Over 11 years of follow-up in 4 million Norwegians, the beta 2AR agonist salbutamol, a brain-penetrant asthma medication, was associated with reduced risk of developing PD (rate ratio, 0.66; 95% confidence interval, 0.58 to 0.76). Conversely, a beta 2AR antagonist correlated with increased risk. beta 2AR activation protected model mice and patient-derived cells. Thus, beta 2AR is linked to transcription of a-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.