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 K Xiang; Jean-Christophe Rochet; Anders Engeland; Patrizia Rizzu; Peter Heutink; Tim Bartels; Dennis J Selkoe; Barbara J Caldarone; Marcie A Glicksman; Vikram Khurana; Birgitt Schüle; David S Park; Trond Riise; Clemens R Scherzer

doi:10.1126/science.aaf3934

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

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

Authors

Shuchi Mittal^{1

2

3}, Kjetil Bjørnevik^{4

5}, Doo Soon Im⁶, Adrian Flierl⁷, Xianjun Dong^{1

2

3}, Joseph J Locascio^{1

8}, Kristine M Abo¹, Elizabeth Long¹, Ming Jin^{2

3}, Bing Xu⁹, Yang K Xiang⁹, Jean-Christophe Rochet¹⁰, Anders Engeland^{4

11}, Patrizia Rizzu¹², Peter Heutink¹², Tim Bartels^{2

3}, Dennis J Selkoe^{2

3}, Barbara J Caldarone^{3

13}, Marcie A Glicksman¹³, Vikram Khurana^{2

3

14}, Birgitt Schüle⁷, David S Park⁶, Trond Riise^{4

5}, Clemens R Scherzer^{15

2

3}

Affiliations

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. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetylation
Adrenergic beta-1 Receptor Agonists / pharmacology
Adrenergic beta-Antagonists / pharmacology
Adrenergic beta-Antagonists / therapeutic use
Albuterol / pharmacology
Albuterol / therapeutic use
Animals
Cell Line, Tumor
Enhancer Elements, Genetic
Gene Expression Regulation* / drug effects
Histones / metabolism
Humans
Ligands
Mice
Neuroprotective Agents / pharmacology
Norway / ethnology
Parkinson Disease / drug therapy
Parkinson Disease / ethnology*
Parkinson Disease / genetics*
Promoter Regions, Genetic
Propranolol / pharmacology
Propranolol / therapeutic use
Receptors, Adrenergic, beta-2 / genetics
Receptors, Adrenergic, beta-2 / metabolism*
Risk
Substantia Nigra / metabolism
Transcription, Genetic / drug effects
alpha-Synuclein / genetics*

Substances

Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Antagonists
Histones
Ligands
Neuroprotective Agents
Receptors, Adrenergic, beta-2
SNCA protein, human
alpha-Synuclein
Propranolol
Albuterol

Abstract

Publication types

MeSH terms

Substances

Grants and funding