Using adult stem cells, researchers have generated the type of human neuron specifically damaged by Parkinson’s disease (PD) and used various drugs to stop the damage. Working as part of a National Institute of Neurological Disorders and Stroke consortium, the team created three lines of induced pluripotent stem (iPS) cells derived from the skin cells of adults with PD. Two of the cell lines had the mutated LRKK2 gene, a hallmark of the most common genetic cause of PD.
“Our study suggests that some failed drugs should actually work if they were used earlier, and especially if we could diagnose PD before tremors and other symptoms first appear,” said Ted M. Dawson, M.D., Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine.
Dawson said the ability to experiment with a form of “Parkinson’s in a dish” should lead to further understanding of how the disease originates, develops and behaves in humans.
Although scientists have been able to stop the disease in mice, the compounds used to do so have not worked in people, suggesting that human PD behaves differently than animal models of the disorder. Here, researchers began with the belief that PD is strongly linked to disruption of the dopamine neurons’ mitochondria, the energy-making power plants of the cells. Mitochondria undergo regular turnover in which they fuse together and then split apart. Normal neurons make new mitochondria and degrade older mitochondria in a balanced way to supply just the amount of energy needed. Parkinson's Disease, Dawson said, is believed to damage this system, leaving too few functional mitochondria and producing too many brain-damaging oxygen-free radicals.
The team looked for — and found — evidence of impaired mitochondria in the neurons they derived from PD patients. They also found that the neurons they generated from PD patients were more susceptible to stressors, such as the pesticide rotenone, placed on them in the lab. Those neurons were more likely to become damaged or to die than the neurons derived from the skin of healthy individuals.
Satisfied that their stem cell-generated neurons were behaving like dopamine brain cells, the scientists next set out to see if they could slow the damage occurring in the PD neurons by introducing various compounds to the cells. They tested Coenzyme Q10, rapamycin and the LRRK2 kinase inhibitor GW5074, all of which are known to reverse mitochondrial defects in animals. The cells responded favorably to all three treatments, preventing stressors from continuing to damage the mitochondria.
More than 20 clinical trials have been conducted in people with PD using drugs designed to slow the disease’s progression. All of them have failed. Coenzyme Q10 worked in the iPS cells derived from PD patients. “This suggests the need to treat people before they actually manifest the disease,” said Dawson. He cautioned that the consortium’s work is at its earliest stages, and that application of the findings may be years away. Among other barriers is the lack of a way to diagnose PD before tremors and other symptoms appear. Although several gene mutations have been linked to PD, there could be more, making a simple genetic test for the disease unlikely in the near term. Moreover, the majority of PD has no known specific genetic link.
Adapted from the John's Hopkins School of Medicine announcement.