Cancer Drug May Prevent Parkinson's Disease

The chemotherapy agent imatinib (Gleevac) has shown promise in preclinical trials as a potential treatment for neurological syndromes such as Parkinson's disease that result from the intracellular build-up of toxic compounds.

Imatinib, also known as STI-571, is a c-Abl-family kinase inhibitor. As such, it prevents the phosphorylation of the enzyme parkin, maintaining parkin in a catalytically active and protective state. Parkin's role is to label "garbage proteins” for removal from the cell. When parkin fails to function, either through mutation of its gene or through inhibition by overexpressed c-Abl kinase, the buildup of toxic compounds can kill neurons, which leads to Parkinson's disease.

In the current study, investigators at Johns Hopkins University (Baltimore, MD, USA) examined the effect of imatinib on cultures of neuron-like cells and on a mouse model of Parkinson's disease. They reported in the September 7, 2010, online edition of the journal the Proceedings of the [U.S.] National Academy of Sciences (PNAS) that in cell cultures, active c-Abl significantly decreased parkin's ability to tag waste proteins. However, incubation of these cells with STI-571 prevented c-Abl's inhibition of parkin's function.

In a line of mice genetically engineered to lack the gene for c-Abl, parkin activity was maintained and it protected the animals against any significant loss of neurons. In addition, toxic elements were found to have accumulated in the brains of patients that had died from Parkinson's disease. Analysis of neurons from these brains revealed elevated levels of c-Abl.

"Our new appreciation of c-Abl's role in sporadic Parkinson's disease suggests that we can give brain-permeable inhibitors of c-Abl to maintain parkin's normal protective function,” said senior author Dr. Ted Dawson, professor of neurodegenerative diseases at Johns Hopkins University. "The testing of these already approved, well-tolerated drugs for a new use — as a neuroprotective treatment for Parkinson's disease — is a potentially exciting therapeutic arc that should be pursued.”

"With people living longer, lots more people are developing this common, debilitating neurological disorder,” Dr. Dawson said. "Now that we know the mechanism, it is important that we explore new, effective therapies that can slow or stop its progression.”

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