Here’s some more news on the Parkinson’s front, with a possible risk factor (and possible protective agent) both coming from an unexpected direction. It’s been known for quite a while now that the alpha-synuclein protein is deeply involved in the pathology of the disease – precipitated masses of it are found apparently killing off cells in the affected region of the brain (it’s the main constituent of Lewy bodies), and people with higher copy numbers of the gene for it are at greater risk for developing the disease in the first place. But just what goes wrong with its production and handling in Parkinson’s is still a matter of debate.
A large multicountry research team reports that the beta-2 receptor, of all things, is a regulator of the SNCA gene that codes for the synuclein protein. A screen for alpha-synuclein protein expression was developed in neuronal cell cultures, and on testing a large selection of known drugs and biomolecules, metaproteronol (a beta-2 agonist) turned out to significantly lower the levels of the protein and its associated mRNA. Other beta-2 agonists replicated the result, fortunately including ones with better brain penetration, and with these the effect also carried over into whole-animal studies in mice. It worked the other way, too – propranolol, a classic beta-antagonist, actually raised alpha-synuclein levels in the same fashion. The same effects were even more pronounced in cells derived from a patient carrying a triplication of the SNCA gene, and administration of an agonist even protects mice neurons to exposure to MPTP, the classic Parkinson’s-inducing model. Digging deeper, this all seems to be mediated by epigenetic marking (acetylation) on lysine-27 of histone-3 protein, which the promoter region of the SNCA gene appears to be very sensitive to.
What’s most remarkable about this paper, though, is that it comes with human data. “How so?”, you’re probably wondering, given the time and expense it takes to get a trial launched. But the Norwegian co-authors provide data from that country’s public health system. Scanning across the entire population of Norway, they find that use of salbutamol (a common beta-2 agonist, often prescribed for asthma) is associated with lower risk of Parkinson’s, and that propranolol, the antagonist, is associated with an even higher risk of developing the disease. The team does a good job of trying to account for other possible confounding factors (asthma itself, education and economic levels, history of smoking and other risk factors, etc.), and the correlations stand up to all of these.
This is definitely something to think about, then. A trial of beta-adrenoceptor ligands in Parkinson’s patients would be comparatively easy to get off the ground, and I hope that something like this is in the works now. It’s going to be a balancing act between their apparent effects on alpha-synuclein and their other effects (cardiovascular, etc.), but this hypothesis is very much worth testing. And if it continues to hold up, then it’s likely to affect clinical practice, too – at the very least, anyone who might be otherwise at risk for Parkinson’s should avoid beta-antagonists.