β2 agonists lower SNCA

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Shamsher Mittal, Kari Bjørnevik, Trond Riise, Clemens Scherzer and colleagues (24 authors, Harvard/Brigham and Women's Hospital and the University of Bergen). Science 357:891–898, 1 September 2017. Funders named: the Michael J. Fox Foundation, the US National Institute of Neurological Disorders and Stroke, the US Department of Defense and others.

What happened

Extra copies of SNCA cause Parkinson's (landmark 14), and a risk variant acts on an SNCA enhancer (landmark 49). The team screened for what controls the gene and found the beta-2 adrenergic receptor. Drugs that activate this receptor (salbutamol, clenbuterol, metaproterenol) reduced SNCA output; blockers (propranolol) raised it. Clenbuterol also protected mice treated with the toxin MPTP.

• Norwegian data. Over 11 years in the whole Norwegian population (about 4 million), 619,863 salbutamol users had a rate ratio of 0.66 (95% CI 0.58–0.76) for Parkinson's, and 14,794 propranolol users 2.20 (1.62–3.00). Lagging propranolol exposure by 1–2 years reduced the ratio to 1.82, which the authors said made reverse causation an unlikely main explanation.
• Dispute. Propranolol is prescribed for tremor, so early undiagnosed Parkinson's could cause the prescription (reverse causation). An Israeli study of 11,314 cases (Gronich et al., Mov Disord 2018) also found lower risk with beta-2 agonists (rate ratios about 0.5–0.9) and higher risk with non-selective beta-blockers. But a 2025 review of 22 studies (Szmigiel et al., Pharmacoepidemiology and Drug Safety) found pooled propranolol risk 2.36 (1.66–3.36) and salbutamol 0.88 (0.77–1.01), not statistically significant, with 20 of 22 studies at high risk of bias in at least one area.

Why it moved us toward a cure

It offered an existing, cheap drug class as a way to turn synuclein down, which is the same logic as the lowering drugs in landmark 29. The weak replication means it is a lead, not a treatment.

Outcome

Open and contested. No Parkinson's trial of a beta-2 agonist was found on ClinicalTrials.gov. No correction or retraction was found; four commentaries accompanied the paper (Europe PMC).

Sources

• Mittal et al., Science 2017, DOI 10.1126/science.aaf3934, PMID 28860381 (abstract via Europe PMC; Norwegian figures and funding from the author manuscript, PMC5761666)
• Gronich et al., Mov Disord 2018, DOI 10.1002/mds.108, PMID 30311974 (abstract via Europe PMC)
• Szmigiel et al., Pharmacoepidemiol Drug Saf 2025, DOI 10.1002/pds.70140, PMID 40200766 (abstract via Europe PMC; LSHTM repository PDF)
• Not yet verified: the Gronich paper's lagged analysis for salbutamol (its abstract is cut off in the source read).