Alpha-synuclein is one of the most prevalent proteins found in human brains. It is also the one that when it fails to conform to its normal configuration, or mis-folds, contributes to the neurodegeneration seen in PARKINSON’S DISEASE. Researchers at the University of Alabama led by Andrew West, Ph.D. think they may have found a key to prevent alpha-synuclein from misfolding and aggregating.
The gene LRRK2 has been linked to PARKINSON’S DISEASE and West’s lab demonstrated that the known mutations of this gene all increase its activity. Other studies have shown that it is related to alpha-synuclein in several ways. This study has shown that blocking the expression of LRRK2 in mouse models that are genetically very similar to human models, blocked the over-expression of alpha-synuclein. Blocking alpha-synuclein may prevent the death of dopamine producing cells in the substantia nigra, thus offering a potential treatment to prevent or slow the progress of PARKINSON’S DISEASE. The search for a drug to inhibit the expression of LRRK2 is now underway.
LRRK2 is known to be significantly involved in the genetic forms of PARKINSONS, in populations of Ashkenazy Jews from Eastern Europe and from Mediterranean ethnic populations such as the Berbers of North Africa, but is not as highly involved in non inherited forms of the disease. Still, West’s team thinks LRRK2 has more than one method of action as seen in the genetic forms. It may interact with alpha-synuclein in other ways.
He asks, “What would happen if you simply remove all LRRK2 activity? Modern approaches allow us to approximate what a perfect drug would do in rats and mice. We think LRRK2 is plugging into PARKINSON’S DISEASE in more than one way. It is making the disease more likely to happen and making it progress faster when it does happen. So we think knocking out LRRK2 will do the opposite–slow the disease or make it much less likely to develop.”
Simply slowing the progress of the disease would be a major break through. It could extend the length of time that levodopa effectively alleviates the symptoms and could even reduce or eliminate some of the side effects that can sometimes be worse than the disease.
Southern Research Institute is pharmaceutical research company partnering with Dr. West’s lab to develop a drug to inhibit LRRK2. They hope to be able to test it in humans early next year.
J. P. L. Daher, L. A. Volpicelli-Daley, J. P. Blackburn, M. S. Moehle, A. B. West.Abrogation of -synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proceedings of the National Academy of Sciences, 2014; DOI: 10.1073/pnas.1403215111
Review by Marcia McCall
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