| Literature DB >> 28860381 |
Shuchi Mittal1,2,3, Kjetil Bjørnevik4,5, Doo Soon Im6, Adrian Flierl7, Xianjun Dong1,2,3, Joseph J Locascio1,8, Kristine M Abo1, Elizabeth Long1, Ming Jin2,3, Bing Xu9, Yang K Xiang9, Jean-Christophe Rochet10, Anders Engeland4,11, Patrizia Rizzu12, Peter Heutink12, Tim Bartels2,3, Dennis J Selkoe2,3, Barbara J Caldarone3,13, Marcie A Glicksman13, Vikram Khurana2,3,14, Birgitt Schüle7, David S Park6, Trond Riise4,5, Clemens R Scherzer15,2,3.
Abstract
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.Entities:
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Year: 2017 PMID： 28860381 PMCID： PMC5761666 DOI： 10.1126/science.aaf3934
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728