Journal Article

DZNE-2020-05801

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease.

Mittal, S. ; Bjørnevik, K. ; Im, D. S. ; Flierl, A. ; Dong, X. ; Locascio, J. J. ; Abo, K. M. ; Long, E. ; Jin, M. ; Xu, B. ; Xiang, Y. K. ; Rochet, J.-C. ; Engeland, A. ; Rizzu, P.DZNE* ; Heutink, P.DZNE* ; Bartels, T. ; Selkoe, D. J. ; Caldarone, B. J. ; Glicksman, M. A. ; Khurana, V. ; Schüle, B. ; Park, D. S. ; Riise, T. ; Scherzer, C. R. (Corresponding author)

2017
Assoc.60841 Washington, DC

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Please use a persistent id in citations: doi:10.1126/science.aaf3934

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.

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

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Contributing Institute(s):

1. Applied Genomics of Neurodegenerative Diseases (AG Rizzu)
2. Genome Biology of Neurodegenerative Diseases (AG Heutink 1)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)
2. 345 - Population Studies and Genetics (POF3-345) (POF3-345)

Appears in the scientific report 2017

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; IF >= 60 ; JCR ; SCOPUS ; Web of Science Core Collection ; Zoological Record

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