Doorways to Discovery
November 11, 2014
His optimism stems from several recent discoveries. One is the role of the enzyme tyrosine kinase c-Abl in inactivating a protein called parkin, which causes toxic cellular debris to accumulate in dopamine cells, leading to dopamine cell death. (Parkinson’s disease symptoms are caused by a selective loss of dopamine neurons in the substantia nigra of the brain.) In new work, Dawson found that c-Abl can itself be inhibited, which would leave parkin to carry out its normal job of degrading the cellular waste.
Crucially, c-Abl also causes a form of leukemia. “What is exciting here,” says Dawson, “is that potent inhibitors have been developed to interfere with the c-Abl activity and successfully treat leukemia. Based on our data in a mouse model of Parkinson’s, we believe that these c-Abl inhibitors should be able to slow the progression of Parkinson’s, too.” He is also looking for biomarkers in cerebrospinal fluid that could be used to evaluate the impact of these inhibitors on Parkinson’s.
Dawson and colleagues are trying to determine which of the c-Abl-inhibiting drugs that are approved by the FDA for leukemia treatment have the best chance of success in Parkinson’s. The researchers found that some c-Abl inhibitors are better at protecting dopamine neurons and restoring behavior deficits in mice than others—“probably due to better brain permeability,” says Dawson.
Challenge: To slow progression of Parkinson’s disease.
Approach: Dawson is performing testing in mice of an enzyme inhibitor approved for leukemia.
Progress: Dawson and team are comparing the effectiveness of a variety of brain-permeable c-Abl inhibitors and expect to be testing treatments in patients with Parkinson’s soon.
