A New Piece of the Parkinson’s Puzzle
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.
Get the whole story by Derek Lowe (September 5, 2017) on http://blogs.sciencemag.org/pipeline/archives/2017/09/05/a-new-piece-of-the-parkinsons-puzzle