Molecule interacts with prion proteins to alter cell behaviour

Researchers study prion interactions to understand how they affect neighbouring cell behaviour

Amy Hewko - 16 April 2014

David Westaway and Jack Jhamandas, two researchers with the Faculty of Medicine & Dentistry, have identified a molecule that interacts with prion proteins to alter the behaviour of potassium channels.

Potassium channels are multicomponent cells that slow down the electrical signals brain cells use to communicate with each other. Westaway and Jhamandas' study examined potassium channel Kv4.2, a major channel that determines whether or not a brain cell will send a signal. What they discovered was that when prions are in close proximity to this type of potassium channels, the strength and speed of the signal increases rather than decreases.

Prions play a role in the development of neurodegenerative diseases, including bovine spongiform encephalopathy, or mad cow disease, and Creutzfeld-Jakob disease. It is not fully known what role prions play in regulating communication between individual cells, says Jhamandas, but as they are now implicated in Alzheimer's disease, it is vital to understand prion activity before researchers can move toward clinical treatment of related neurodegenerative diseases.

"Knowledge of the processes that shape the activity of individual brain cells is key to understanding how whole organisms work," says Jhamandas, a professor in the Department of Medicine's neurology division. "Our findings provide important information on how prion proteins influence normal brain communication and what goes wrong in neurodegenerative diseases."

To understand why prions reverse the natural behaviour of potassium channels, Jhamandas and Westaway genetically engineered channels that lacked different components. Robert Mercer, a PhD student in Westaway's lab, led this process, which involves attaching each individual component of the potassium channel to a host cell called HEK.

"We introduced the components one by one into cells that do not have the full spectrum of electrical activity that a brain cell would. The advantage to HEK cells is that we can focus on a particular kind of activity," says Westaway, the director of the Centre for Prion and Protein Folding Diseases. He noted that quality control measures were conducted to ensure the cells were properly assembled.

Prions were then introduced to the genetically engineered potassium channels. When a molecule called DPP6 was absent, nearby prions did not cause the electrical signals to speed through the potassium channel as they would in naturally formed cells. Electrical signals were measured by Li Ma, a research associate in Jhamandas' lab.

In the future, Westaway and Jhamandas hope to introduce amyloid proteins, which are involved in the development of Alzheimer's disease, into the HEK model. Amyloid proteins interact with both prions and potassium channels, though Jhamandas says the mechanism that causes the interaction is unknown.

"It's very difficult to understand the operation of membrane channels, which serve as a conduit for all communication in the brain," Jhamandas noted. "They're not just a slit in the cell. They're made of different proteins and each no contributes to how the cell functions. Understanding these molecular gateways will give us new options for treatments."

The study was published in the Journal of Biological Chemistry on Dec 27, 2013.