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Newly Created Stem Cell Lines Could Offer Insight into Parkinson’s

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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 Parkinson's. Two of the cell lines had the mutated LRKK2 gene, a hallmark of the most common genetic cause of the disease.

The researchers then used the iPS cells to create dopamine neurons, which bear the brunt of Parkinson's.

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 Parkinson's behaves differently than animal models of the disorder.

The researchers began with the belief that Parkinson's 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 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 Parkinson's patients. They also found that the neurons they generated from these 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 Parkinson's 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.

"This suggests the need to treat people before they actually manifest the disease," Dawson said.

He cautioned that the consortium's work is at its earliest stages and that application of the findings may be years away.

The results of the experiment were published in Science Translational Medicine.

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Johns Hopkins Medicine