Death of Dopamine-Producing Cells in Parkinson Disease Linked with Mitochondrial Damage

Scientists have used a synthetic form of a recreational heroine-like drug developed back in the 1980s to demonstrate that dopamine-producing nerve cell death caused by Parkinson disease may be due to mitochondrial damage. Using cultured cells, the Washington University School of Medicine researchers found that the toxin MPP+ stopped the circulation of mitochondria in dopamine-producing cell axons, leading to the axonal withering and subsequently cell death. 

Karen O’Malley, Ph.D., and colleagues describe their findings in the Journal of Neuroscience. Their paper is titled “The Parksinonian mimetic, MPP+, specifically impairs mitochondrial transport in dopamine-producing axons.”

MPP+ is derived from a synthetic form of heroin that caused Parkinson disease-like symptoms in people who took the drug. When applied to cultured dopamine-producing neurons, the toxin caused mitochondria to stop trafficking along the axon within about 30 minutes, although other axonal transport systems continued to function.

Looking more closely at the mitochondria in treated cells, the researchers found that in some cases mitochondria seemed to be moving back toward the cell body, against the flow of other molecules and organelles, which suggested they were being trafficked back for repair. Further investigation showed that the mitochondria had lost their ability to maintain their membrane potential.  

“Much of the research into Parkinson disease treatments is focused on saving the bodies of these cells, but our results suggest that keeping axons healthy also is essential," Dr. O’Malley notes. "When axons die back, dopamine is no longer delivered to the neurons that need it. The cell body also has fewer connections to other cells, and it needs those connections to survive.”

Interestingly, the toxin had no effect on transportation of mitochondria in other types of nerve cells. While the specificity for dopamine-producing neurons has still to be worked out, a clue may lie in the team’s observation that in comparison with other types of nerve cells, mitochondria in this type of neuron are smaller in size and travel three times more slowly.

The researchers subsequently demonstrated that that the antioxidant N-acetyl cysteine, which is effective in animal models of Parkinson disease, seemed to block the toxin’s effects. They are currently investigating whether two genes linked to Parkinson disease affect mitochondria damaged by the toxin.