“Jekyll and Hyde” enzyme has potential for countering cancer and Alzheimer’s

Press/Media: Press / Media

24/10/2016

An enzyme that helps tumour cells thrive under stress has the opposite effects on besieged neurons in Alzheimer’s Disease – it actually hastens their death.

The discovery of the enzyme’s “Jekyll and Hyde” dichotomy by UBC Faculty of Medicine and BC Cancer Agency scientists is welcome news, because it means blocking that enzyme could be beneficial in either case – in cancer, by weakening malignant cells’ ability to withstand stress, and in Alzheimer’s disease, by enabling brain cells to withstand assault from toxic protein fragments.

The link is one of several to have emerged in recent years between cancer and neurodegenerative diseases, providing hope that progress in one field could pay off in another.

“We get so siloed in our research, thinking only about the specific thing we’re working on,” said Poul Sorensen, a Professor in the Department of Pathology and Laboratory Medicine and Senior Scientist at the BC Cancer Agency, who was the senior author on the article published in this month’s neurosciences journal, Acta Neuropathologica. “Sometimes, it really makes sense to take a deep breath and ask ourselves if we’re missing something that could be helpful to understand other diseases.”

In 2013, Dr. Sorensen, an investigator with the Michael Cuccione Childhood Cancer Research Program at BC Children’s Hospital, found that the enzyme, eEF2K, allows cancer cells to survive in the face of nutrient scarcity – a common condition for cancer cells because they multiply so rapidly, often outstripping available sources of energy.

Encouraged by a subsequent discovery that a molecule that protects against childhood cancers might also protect against Huntington’s disease, and the addition to his lab of postdoctoral fellow Asad Jan, who had a background in neuronal diseases, Dr. Sorensen began exploring whether eEF2K played a role in Alzheimer’s disease. Both scientists figured the enzyme had the same protective effect on neurons as it did on tumour cells, and that neurons simply cannot produce enough of it to counter the toxic effects of amyloid-beta protein fragments – the main driver of Alzheimer’s disease.

Instead, to their surprise, Dr. Sorensen and Dr. Jan found that mouse models of Alzheimer’s disease had elevated levels of eEF2K activity in their brains. They also found higher activity levels of the enzyme in brain tissue from deceased Alzheimer’s patients.

The researchers analyzed the brain cells of mice that were genetically engineered to be eEF2K-deficient. The neurons, when exposed to amyloid-beta protein fragments, remained viable and continued to grow.

Working with the lab of Stefan Taubert, an Associate Professor in the Department of Medical Genetics, the scientists also observed the behavior of genetically-engineered worms that produced amyloid-beta protein fragments – in effect, a worm model of Alzheimer’s disease. As expected, such worms did not move toward food-like odors, indicating that they were neurologically impaired. But worms that were also engineered to be eEF2K-deficient behaved normally – they moved toward the attractive odors, a sign that they were neurologically healthy, and thus had resisted the toxic effects of the amyloid-beta protein fragments.

Dr. Sorensen believes that eEF2K has an important role in neuronal activity, controlling the transmission of signals from one neuron to the next. But amyloid protein fragments somehow “hijack” eEF2K and send it into overdrive, creating excess oxidative stress – a series of biochemical reactions that are damaging to a cell’s proteins, membranes and genes.

The next step for Dr. Sorensen and Dr. Jan is to do the same thing with mice as they did with worms – genetically engineering mice that are afflicted by amyloid-beta fragments, but also unable to produce eEF2K, to see if they resist the debilitating, neurodegenerative symptoms of Alzheimer’s disease.

“We think there is a therapeutic window here,” Dr. Sorensen says. “The good news is, the clinical implication is the same, whether it’s cancer or Alzheimer’s disease – blocking eEf2k would be the goal, but for very different reasons.”

References

  • "Jekyll and Hyde” enzyme has potential for countering cancer and Alzheimer’s

References

Title"Jekyll and Hyde” enzyme has potential for countering cancer and Alzheimer’s
Degree of recognitionLocal
Media typeWeb
CountryCanada
Date24/10/2016
PersonsJan Asad
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ID: 117635784