β2-Adrenoreceptor is a regulator of the α-synuclein gene driving risk of Parkinson's disease.
Shuchi MittalKjetil BjornevikDoo Soon ImAdrian FlierlXianjun DongJoseph J LocascioKristine M AboElizabeth LongMing JinBing XuYang K XiangJean-Christophe RochetAnders EngelandPatrizia RizzuPeter HeutinkTim BartelsDennis J SelkoeBarbara J CaldaroneMarcie A GlicksmanVikram KhuranaBirgitt SchüleDavid S ParkTrond RiiseClemens R ScherzerPublished in: Science (New York, N.Y.) (2018)
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.
Keyphrases
- copy number
- dna methylation
- gene expression
- transcription factor
- genome wide
- mitochondrial dna
- induced apoptosis
- chronic obstructive pulmonary disease
- healthcare
- emergency department
- adverse drug
- genome wide identification
- lung function
- cell cycle arrest
- risk assessment
- multiple sclerosis
- allergic rhinitis
- metabolic syndrome
- brain injury
- drug delivery
- cell death
- high fat diet induced
- histone deacetylase
- cerebral ischemia
- electronic health record
- drug induced