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Science. 2017 Sep 1;357(6354):891-898. doi: 10.1126/science.aaf3934.

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

Author information

1
Neurogenomics Laboratory and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
2
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
3
Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.
4
Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
5
The Norwegian Multiple Sclerosis Competence Center, Department of Neurology, Haukeland University Hospital, Norway.
6
Brain and Mind Research Institute, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
7
The Parkinson's Institute and Clinical Center, Sunnyvale, CA 94085, USA.
8
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.
9
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.
10
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
11
Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway.
12
German Center for Neurodegenerative Diseases (DZNE), Tübingen 72076, Germany.
13
Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA 02115, USA.
14
Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
15
Neurogenomics Laboratory and Parkinson Personalized Medicine Program, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. cscherzer@rics.bwh.harvard.edu.

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.

PMID:
28860381
PMCID:
PMC5761666
DOI:
10.1126/science.aaf3934
[Indexed for MEDLINE]
Free PMC Article

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