Finding a way to energize dopamine cells

Dr. Mireille Khacho

Dr. Mireille Khacho, a uOttawa postdoctoral fellow in Dr. Ruth Slack’s lab, grew up with Parkinson’s, as her grandmother suffered with the disease for 30 years.

Parkinson's is a degenerative disease that results from the depletion of dopamine-producing cells in the brain. To fix something, you need to understand how it works. That’s what the Parkinson’s research team has focused on: understanding why dopamine neurons are targeted and affected by Parkinson’s disease.

“One of the fundamental things we wanted to learn was what it is about these specific neurons that make them so sensitive. Why is it that these neurons are dying?” said Dr. Khacho.

Neurons need energy. Her team discovered that dopamine neurons use up lots of energy, which is provided by mitochondria – the energy making factories in cells.  What her team found is that these particular cells use their mitochondria at burn-out capacity. When dopamine neurons are stressed and need more energy their mitochondria become overtaxed and begin making reactive oxygen species. Reactive oxygen species  are toxic to the cell and cause these dopamine neurons to die.

Dr. Khacho uses a car analogy. If a car engine always ran at maximum capacity on flat terrain, then when it reached a hill, the car couldn’t get more energy to get up the hill. That’s dopamine and mitochondria, however, Dr. Khacho said, “We have a way of making the engine work better.Donate now to PIPR

She has found a way to make cells work better – strengthening the engine to make mitochondria stronger, more efficient, and more resilient in making more energy. Dr. Khacho said, “We have found a way to genetically manipulate the mitochondria in the lab, but if we can find a drug to make mitochondria stronger and more efficient in the way we want them to, then this would be a way to stop these dopamine neurons from dying.”

The next step is to find existing drugs that will boost mitochondrial energy. Dr. Khacho and her team want to screen and repurpose drugs already in use, because existing drugs have been approved and their side effects are already known. Dr. Khacho’s team is looking to screen any drugs that test positive. Mitochondria change their shape when they are not healthy, so it’s easy to screen drugs. They will  test these drugs on cultured neurons and see the reaction of cells in models of Parkinson’s in a laboratory petri dish.

Once the researchers have positively identified neurons surviving because of a certain drug, then they plan to take those results to the next stage and test on animal models of Parkinson’s disease. Animals are not given any drug treatment until there are very positive results on the genetic models in the dish.  The animals will then be studied to see if they endure less neurodegeneration and have improved cognitive function. From there, testing will move to humans in the clinic, but it is several years before research reaches that stage. The team is doing this important basic science research in collaboration with researchers at CHEO, where a lab is set up to study mitochondrial morphology changes.

“Basic research is so important,” says Dr. Khacho. “It helps industry make strides in developing treatments.”

This is one of the discoveries made by researchers at The Ottawa Hospital that will propel our understanding of Parkinson’s disease. Dr. Khacho and Dr. Slack’s work on how to make mitochondria more efficient was published in Nature Communications in 2014.   Made-in-Ottawa research is making big strides academically, eventually having a clinical impact.