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?2-Adrenoreceptor is a regulator of the ?-synuclein gene driving risk of Parkinson's disease.

ABSTRACT: Copy number mutations implicate excess production of ?-synuclein as a possibly causative factor in Parkinson's disease (PD). Using an unbiased screen targeting endogenous gene expression, we discovered that the ?2-adrenoreceptor (?2AR) is a regulator of the ?-synuclein gene (SNCA). ?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 ?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 ?2AR antagonist correlated with increased risk. ?2AR activation protected model mice and patient-derived cells. Thus, ?2AR is linked to transcription of ?-synuclein and risk of PD in a ligand-specific fashion and constitutes a potential target for therapies.

SUBMITTER: Mittal S

PROVIDER: S-EPMC5761666 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Mittal Shuchi S Bjørnevik Kjetil K Im Doo Soon DS Im Doo Soon DS Flierl Adrian A Dong Xianjun X Locascio Joseph J JJ Abo Kristine M KM Long Elizabeth E Jin Ming M Xu Bing B Xiang Yang K YK Rochet Jean-Christophe JC Engeland Anders A Rizzu Patrizia P Heutink Peter P Bartels Tim T Selkoe Dennis J DJ Caldarone Barbara J BJ Glicksman Marcie A MA Khurana Vikram V Schüle Birgitt B Park David S DS Riise Trond T Scherzer Clemens R CR

Science (New York, N.Y.) 20170901 6354

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 (<i>SNCA</i>). β2AR ligands modulate <i>SNCA</i> 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-pe ...[more]

PMID: 28860381

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

?2-Adrenoreceptor is a regulator of the ?-synuclein gene driving risk of Parkinson's disease.

Publications

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

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