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{beta}2-Adrenoreceptor is a regulator of the {alpha}-synuclein gene driving risk of Parkinsons disease

Copy number mutations implicate excess production of α-synuclein as a possibly causative factor in Parkinson’s disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the β2-adrenoreceptor (β2AR) is a regulator of the α-synuclein gene (SNCA). β2AR 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 β2AR 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 β2AR antagonist correlated with increased risk. β2AR activation protected model mice and patient-derived cells. Thus, β2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

Authors:   Shuchi Mittal; Kjetil Bjørnevik; Doo Soon Im; Adrian Flierl; Xianjun Dong; Joseph J. Locascio; Kristine M. Abo; Elizabeth Long; Ming Jin; Bing Xu; Yang K. Xiang; Jean-Christophe Rochet; Anders Engeland; Patrizia Rizzu; Peter Heutink; Tim Bartels; Dennis J. Selkoe; Barbara J. Caldarone; Marcie A. Glicksman; Vikram Khurana; Birgitt Schüle; David S. Park; Trond Riise; Clemens R. Scherzer
Journal:   Science
Volume:   357
edition:   6354
Year:   2017
Pages:   891
DOI:   10.1126/science.aaf3934
Publication date:   01-Sep-2017
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