TY - JOUR
T1 - β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease
AU - Mittal, Shuchi
AU - Bjørnevik, Kjetil
AU - Im, Doo Soon
AU - Flierl, Adrian
AU - Dong, Xianjun
AU - Locascio, Joseph J.
AU - Abo, Kristine M.
AU - Long, Elizabeth
AU - Jin, Ming
AU - Xu, Bing
AU - Xiang, Yang Kevin
AU - Rochet, Jean Christophe
AU - Engeland, Anders
AU - Rizzu, Patrizia
AU - Heutink, Peter
AU - Bartels, Tim
AU - Selkoe, Dennis J.
AU - Caldarone, Barbara J.
AU - Glicksman, Marcie A.
AU - Khurana, Vikram
AU - Schüle, Birgitt
AU - Park, David S.
AU - Riise, Trond
AU - Scherzer, Clemens R.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
AB - 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.
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U2 - 10.1126/science.aaf3934
DO - 10.1126/science.aaf3934
M3 - Article
C2 - 28860381
AN - SCOPUS:85029541597
VL - 357
SP - 891
EP - 898
JO - Science
JF - Science
SN - 0036-8075
IS - 6354
ER -