Using adult stem cells, Johns Hopkins researchers and a consortium of colleagues nationwide say they have generated the type of human neuron specifically damaged by Parkinson's disease (PD) and used various drugs to stop the damage.
Their experiments on cells in the laboratory, reported in the July 4 issue of the journal Science Translational Medicine, could speed the search for new drugs to treat the incurable neurodegenerative disease, but also, they say, may lead them back to better ways of using medications that previously failed in clinical trials.
"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," says one of the study's leaders, Ted M. Dawson, M.D., Ph.D., a professor of neurology at the Johns Hopkins University School of Medicine.
Dawson and his colleagues, working as part of a National Institute of Neurological Disorders and Stroke consortium, 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. Induced pluripotent stem cells are adult cells that have been genetically reprogrammed to their most primitive state. Under the right circumstances, they can develop into most or all of the 200 cell types in the human body.
In the laboratory, the consortium scientists used the iPS cells to create dopamine neurons, those that bear the brunt of PD. Around age 60, people who have the disorder typically begin to show symptoms, including shaking (tremors) and difficulty with walking, movement and coordination. In the United States, at least 500,000 people are believed to have PD, and an estimated 50,000 new cases are reported annually.
Dawson says 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. Dawson, director of Johns Hopkins' Institute for Cell Engineering, says the 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.
PD, Dawson says, is believed to damage this system, leaving too few functional mitochondria and producing too many brain-damaging oxygen-free radicals.
Dawson and his colleagues 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.
Dawson says 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," he says.
Dawson cautioned that the consortium's work is at its earliest stages, and that application of the findings may be years away. Among other barriers, he says, is the lack of a way to diagnose PD before tremors and other symptoms appear. In addition, 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.
Other members of the research consortium include Harvard Medical School, Northwestern University's Feinberg School of Medicine, Columbia University, Massachusetts General Hospital, University of Pennsylvania School of Medicine, State University of New York at Buffalo, and the Mayo Clinic in Jacksonville, Fla.
Other Johns Hopkins researchers who contributed to the study include Shaida Andrabi, Ph.D.; Li Chen; Leslie A. Scarffe and Valina L. Dawson, Ph.D.
- O. Cooper, H. Seo, S. Andrabi, C. Guardia-Laguarta, J. Graziotto, M. Sundberg, J. R. McLean, L. Carrillo-Reid, Z. Xie, T. Osborn, G. Hargus, M. Deleidi, T. Lawson, H. Bogetofte, E. Perez-Torres, L. Clark, C. Moskowitz, J. Mazzulli, L. Chen, L. Volpicelli-Daley, N. Romero, H. Jiang, R. J. Uitti, Z. Huang, G. Opala, L. A. Scarffe, V. L. Dawson, C. Klein, J. Feng, O. A. Ross, J. Q. Trojanowski, V. M.- Y. Lee, K. Marder, D. J. Surmeier, Z. K. Wszolek, S. Przedborski, D. Krainc, T. M. Dawson, O. Isacson. Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson's Disease. Science Translational Medicine, 2012; 4 (141): 141ra90 DOI: 10.1126/scitranslmed.3003985
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