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

Shuchi Mittal, Kjetil Bjørnevik, Doo Soon Im, Adrian Flierl, Xianjun Dong, Joseph J. Locascio, Kristine M. Abo, Elizabeth Long, Ming Jin, Bing Xu, Yang Kevin Xiang, Jean Christophe Rochet, Anders Engeland, Patrizia Rizzu, Peter Heutink, Tim Bartels, Dennis J. Selkoe, Barbara J. Caldarone, Marcie A. Glicksman, Vikram KhuranaBirgitt Schüle, David S. Park, Trond Riise, Clemens R. Scherzer

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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 b2-adrenoreceptor (b2AR) is a regulator of the α-synuclein gene (SNCA). b2AR 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 b2AR 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 b2AR antagonist correlated with increased risk. b2AR activation protected model mice and patient-derived cells. Thus, b2AR is linked to transcription of α-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

Original languageEnglish (US)
Pages (from-to)891-898
Number of pages8
JournalScience
Volume357
Issue number6354
DOIs
StatePublished - Sep 1 2017

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Mittal, S., Bjørnevik, K., Im, D. S., Flierl, A., Dong, X., Locascio, J. J., Abo, K. M., Long, E., Jin, M., Xu, B., Xiang, Y. K., Rochet, J. C., Engeland, A., Rizzu, P., Heutink, P., Bartels, T., Selkoe, D. J., Caldarone, B. J., Glicksman, M. A., ... Scherzer, C. R. (2017). β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease. Science, 357(6354), 891-898. https://doi.org/10.1126/science.aaf3934