Scientists Trip Over Potential Breakthrough in Dementia Research

Protein Structure

A study published in Nature Communications this month describes how researchers at the United Kingdom Research Institute at the University of Cambridge stumbled upon a potential target of dementia research. 

Initially, the goal was to investigate whether the protein misfolding seen in neurodegenerative diseases is caused by stress placed upon the protein synthesis process. Instead, the team discovered that stress conditions lead the cell to refold proteins previously misfolded. 

This research was funded by the Portuguese Foundation for Science and Technology, Alzheimer’s Society, Alzheimer’s Research United Kingdom and the Medical Research Council, and distributed through the United Kingdom Dementia Research Institute.

The function of the mammalian endoplasmic reticulum, as taught in nearly every biology class, is protein synthesis. This includes folding any modifications needed and transporting them to the cell’s destination. As a result of the endoplasmic reticulum’s important role, the organelle has become a target in neurodegenerative diseases. 

The logic behind the researchers’ initial hypothesis was that, when pressured to produce an increased number of proteins, stress causes the endoplasmic reticulum begins to misfold proteins as they are being made. However, researchers found this initial hypothesis to be incorrect when they started digging further into whether it could be supported.

Dr. Edward Avezov of the United Kingdom Research Institute explains the serendipitous accident.

“Just like when we get stressed by a heavy workload, so, too, cells can get ‘stressed’ if they’re called upon to produce a large amount of proteins,” he said. “There are many reasons why this might be, for example when they are producing antibodies in response to an infection. We focused on stressing a component of cells known as the endoplasmic reticulum, which is responsible for producing around a third of our proteins – and assumed that this stress might cause misfolding…we were astonished to find that stressing the cell actually eliminated the aggregates – not by degrading them or clearing them out, but by unraveling the aggregates, potentially allowing them to refold correctly.”

To support the new findings, the team began working with Pennsylvania State University and the University of Algarve to develop a way to detect protein misfolding in real-time. The novel method “relies on measuring light patterns of a glowing chemical over a scale of nanoseconds - one billionth of a second.” The technique proved to be instrumental in the discovery. 

Professor Eduardo Melo from the University of Algarve, a leading study author, marveled at the new technique. “It’s fascinating how measuring our probe’s fluorescence lifetime on the nanoseconds scale under a laser-powered microscope makes the otherwise invisible aggregates inside the cell obvious," he said.

Additional speculation questions whether beneficial stress is the underlying reason why some research from Scandinavia suggests that regular sauna use may lower a person’s risk of developing dementia. These new findings may be the backbone of future research in the ongoing search for cures for Parkinson’s, Alzheimer’s and other devastating neurodegenerative diseases.

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