Journal
SCIENCE
Volume 357, Issue 6354, Pages 891-897Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaf3934
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Funding
- Michael J. Fox Foundation
- National Institute of Neurological Disorders and Stroke [U01 NS082157, U01NS095736, R01 NS083845]
- U.S. Department of Defense
- M.E.M.O. Hoffman Foundation
- Prinses Beatrix Spier Fonds
- American Parkinson's Disease Association
- Parkinson's Disease Foundation
- Branfman Family Foundation
- Canadian Institute of Health Research
- Brain Canada/Krembil Foundation
- Heart and Stroke Foundation of Canada
- Multiple System Atrophy Coalition
- Harvard NeuroDiscovery Center
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Copy number mutations implicate excess production of a-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the beta 2-adrenoreceptor (beta 2AR) is a regulator of the a-synuclein gene (SNCA). beta 2AR 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 beta 2AR 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 beta 2AR antagonist correlated with increased risk. beta 2AR activation protected model mice and patient-derived cells. Thus, beta 2AR is linked to transcription of a-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.
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