1. β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson’s disease
- Author
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Mittal, Shuchi, Bjørnevik, Kjetil, Im, Doo Soon, Flierl, Adrian, Dong, Xianjun, Locascio, Joseph J, Abo, Kristine M, Long, Elizabeth, Jin, Ming, Xu, Bing, Xiang, Yang K, Rochet, Jean-Christophe, Engeland, Anders, Rizzu, Patrizia, Heutink, Peter, Bartels, Tim, Selkoe, Dennis J, Caldarone, Barbara J, Glicksman, Marcie A, Khurana, Vikram, Schüle, Birgitt, Park, David S, Riise, Trond, and Scherzer, Clemens R
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurodegenerative ,Biotechnology ,Brain Disorders ,Aging ,Neurosciences ,Acquired Cognitive Impairment ,Genetics ,Parkinson's Disease ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Acetylation ,Adrenergic beta-1 Receptor Agonists ,Adrenergic beta-Antagonists ,Albuterol ,Animals ,Cell Line ,Tumor ,Enhancer Elements ,Genetic ,Gene Expression Regulation ,Histones ,Humans ,Ligands ,Mice ,Neuroprotective Agents ,Norway ,Parkinson Disease ,Promoter Regions ,Genetic ,Propranolol ,Receptors ,Adrenergic ,beta-2 ,Risk ,Substantia Nigra ,Transcription ,Genetic ,alpha-Synuclein ,General Science & Technology - 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.
- Published
- 2017