Treat Parkinson's Disease with a Cancer Drug

Researchers from Johns Hopkins, whose study results were recently published in an early online issue of the Proceedings of the National Academy of Sciences, have found that the brain-protection effects of a molecule are shut down by over-activation of a single protein, allowing for facilitation of the most common Parkinson’s disease type.

The finding, which has the potential to lead to new targets for already-available agents, adds to previous research that showed the protein parkin “protects brain cells by ‘tagging’ certain toxic elements that are then destroyed naturally.” And although mutations in the gene that holds the code for parkin are known to cause rare, familial forms of Parkinson’s disease, the role of parkin in sporadic, late-onset disease has remained unclear, while the prevalence of this type of Parkinson’s disease increases with the aging of our population.

The current study shows that parkin’s activity can be shut down by over-activation of the protein c-Ab1, leading to build-up of brain cell-killing proteins and enabling the progression of Parkinson’s disease.

Knowledge of the cell death contributions made by C-Ab1 isn’t new, with the protein implicated in a number of diseases and the target of several cancer-killing agents, including imatinib.

"Our new appreciation of c-Abl's role in sporadic PD suggests that we can give brain-permeable inhibitors of c-Abl to maintain parkin's normal protective function," said Ted Dawson, MD, PhD, Leonard and Madlyn Abramson Professor in Neurodegenerative Diseases, and scientific director, Johns Hopkins Institute for Cell Engineering. "The testing of these already-approved, well-tolerated drugs for a new use—as a neuro-protective treatment for PD—is a potentially exciting therapeutic arc that should be pursued."

For the study, the researchers labeled certain proteins in neuron-like human cells in culture using the Western blot test, allowing them to see that c-Ab1 shut down parkin’s activity “by measuring the levels of chemical tags on proteins that, in a healthy system, are marked for destruction.” Dawson’s lab previously showed that overabundance of these proteins was selectively toxic to neurons. They found in the current study that the ability of parkin to tag them was significantly decreased when c-Ab1 was active. After incubated the cells with imatinib, know to inhibit c-Ab1, the team found that parkin was fully functional, when compared to cultures that weren’t incubated with the compound.

Moving on to mouse studies, the researchers administered drugs to the rodents that cause Parkinson’s-like traits, allowing them to show that active c-Ab1 shuts down the function of parkin and enables the accumulation of garbage proteins that lead to significant neuron loss. For mice in which c-Ab1 had been knocked out, the loss of neurons was about half that of mice with c-Ab1 that was not disabled. Similar findings were found when the research team compared brain tissue of patients who died with Parkinson’s disease with those of people who died of other causes.

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