This is a very nice piece of work that identifies a link between the beta2-adrenoreceptor (something we often think about in the context of the heart, blood vessels and lungs) and alpha-synuclein (which is thought to be the most important protein in Parkinson's disease).
They start by showing in the laboratory that drugs that act via the beta2-adrenoreceptor influence levels of alpha-synuclein messenger RNA. They go on to show that the effect of drugs that act via the beta2-adrenoreceptor are also associated with an altered risk of Parkinson's disease in an observational study.
First they show that salbutamol (a drug that stimulates the beta2-adrenoreceptor and is used to treat asthma and COPD) is associated with a reduced risk of Parkinson's. Then they show that propranolol (a drug that blocks the beta2-adrenoreceptor and is used to treat fast heart rate and high blood pressure) is associated with a higher risk of Parkinson's.
All in all this is very encouraging and warrants further study. I have two concerns, which the authors do partially discuss, but not really address in the analysis. As well as asthma, salbutamol is used to treat COPD (a disease caused almost exclusively by smoking) and smoking is strongly associated with a reduced risk of Parkinson's. By not adjusting for smoking in the analysis there is no way of knowing for certain that the association seen here is not due to a confounding effect of smoking (although the excellent laboratory work which precedes this allays something of those fears).
The second thing is that we have previously flagged a link between beta-blockers and higher risk of Parkinson's using meta-analysis, and we too observed an increased risk. I always assumed it was driven by reverse causality and that tremor, as a first symptom, may be treated with propranolol before it becomes clear over time that the patient has Parkinson's. The authors partially mitigate this by using a lag time of 1 - 2 years to reduce the risk of reverse causality in cases where tremor preceded the diagnosis of PD by a short period of time. The problem with this is, as we have shown in another study, that tremor may be reported 5 - 10 years before the eventual diagnosis, so a short lag time of 1 - 2 years may be inadequate.
These points aside, there is a lot of very good evidence here to support further exploration of beta2-adrenoreceptors as a therapeutic target. I am really looking forward to seeing more on this...
Science. 2017 Sep 1;357(6354):891-898. doi: 10.1126/science.aaf3934.
Mittal S, Bjørnevik K, Im DS, Flierl A, Dong X, Locascio JJ, Abo KM, Long E, Jin M, Xu B, Xiang YK, Rochet JC, Engeland A, Rizzu P, Heutink P, Bartels T, Selkoe DJ, Caldarone BJ, Glicksman MA, Khurana V, Schüle B, Park DS, Riise T, Scherzer CR.
http://science.sciencemag.org/content/357/6354/891
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.
Copyright © 2017, American Association for the Advancement of Science.
No comments:
Post a Comment