In an attempt to study the root protein mechanism that results in neurodegenerative diseases, a global team of researchers may have figured out the opposite: how to correct the problem.
The scientists—hailing from the U.S., U.K. and Portugal—hypothesized that stress could be a trigger of poor cellular function and ultimately hinder the ability of proteins to be synthesized and correctly “fold.” Over time, misfolded proteins can build up, creating “aggregates,” which impact neuron function.
To test this, they stressed out the endoplasmic reticulum (ER), a membrane structure that produces 30% of the body’s proteins. What the scientists found was that under duress, the endoplasmic reticulum fixed the improper folding. The scientists were shocked.
“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,” said Edward Avezov, a group leader at the UK Dementia Research Institute at the University of Cambridge.
The conclusions of this study, published May 6, are a departure from past indications that ER stress may in fact be a contributor to Alzheimer’s disease. However, those previous findings were deemed inconclusive by scientists at the RIKEN Center for Brain Science in Japan. In a critical review of those findings published in 2018, Shoko Hashimoto and Takaomi C. Saido said more work was needed to fortify results.
“In the course of our studies, the principal conclusion we arrive at is that there is no relationship between AD aetiology and ER stress, and that the role of ER stress in the pathogenesis of AD needs to be carefully addressed in future studies,” they wrote.
To assess the impact of ER stress, scientists tested cells from a monkey, hamster and mouse; the endoplasmic reticulum stress was induced using either a carbohydrate or calcium inhibitor. The scientists were then able to actually visualize the folding of proteins using extremely quick light patterns—we’re talking nanoseconds, or one-billionth of a second or, in plain English: faster than you could ever imagine.
“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,” said University of Algarve Professor Eduardo Melo.
The main proteins that were triggered through the stress were high-shock proteins, often found when cells are stressed or when they’re exposed to higher temperatures. Azerov says this pairs with other findings which correlates a reduced risk of dementia among people in Scandanavian countries where there’s consistent use of saunas.
However, it’s not as simple as it sounds. As exciting as these findings are, Azerov notes that stressing out cells may ultimately cause more harm than good. But still, they present a potential therapeutic avenue should scientists be able to recreate this reaction in the ER without stressing it.