Aggregate Disassembly by Stressed Cells Offers Insights for Neurodegenerative Disease Therapy

It’s often said that a little stress can be good for you. Now, scientists led by a team at the UK Dementia Research Institute, University of Cambridge, have shown that the same may be true for cells. The researchers reported a newly discovered mechanism that might help to prevent the accumulation of protein tangles that are commonly seen in dementia, by reversing the build-up of aggregates, not by eliminating them completely, but rather, by “refolding” them.

“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,” explained research lead Edward Avezov, PhD. “If we can find a way of awakening this mechanism without stressing the cells—which could cause more damage than good—then we might be able to find a way of treating some dementias.”

Avezov and colleagues reported on their findings in Nature Communications, in a paper titled, “Stress-induced protein disaggregation in the endoplasmic reticulum catalyzed by BiP.”

A characteristic feature of neurodegenerative diseases such as Alzheimer’s and Parkinson’s is the build-up of misfolded proteins. These proteins, such as amyloid and tau in Alzheimer’s disease, form aggregates that can cause irreversible damage to nerve cells in the brain.

Protein folding is a normal process in the body, and in healthy individuals cells carry out a form of quality control to ensure that proteins are correctly folded and that misfolded proteins are destroyed. “Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native conformation, whilst eliminating misfolded, aggregation-prone species,” the authors explained. “To avoid the accumulation of cytotoxic aggregates, the biosynthetic organelles (i.e., cytoplasm, the endoplasmic reticulum, or ER, and mitochondria) evolved a multi-layer proteostasis network (PN) that chaperones nascent proteins and rescues or recycles misfolded intermediates.”

In neurodegenerative diseases, this quality control system becomes impaired, with potentially devastating consequences. “Shortfalls of the PN machinery may lead to pathology: protein aggregation accompanies neurodegenerative diseases such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, and frontotemporal dementia,” the team continued. “Neuronally expressed metastable proteins (e.g., Aβ, Tau, or α-synuclein)—with a tendency to oligomerize and consequently aggregate—underlie these conditions.”

As the global population ages, an increasing number of people are being diagnosed with dementia, making the search for effective drugs ever more urgent. However, progress has been slow, with no medicines yet available that can prevent or remove the build-up of aggregates. And as the authors noted, “Understanding how the cell handles aggregation-prone proteins on an organellar level is crucial to rationalizing the disease-related proteostasis impairment.”

The ER is a membrane structure found in mammalian cells. It carries out a number of important functions, including the synthesis, folding, modification, and transport of proteins needed on the surface or outside the cell.

Avezov further explained, “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. There are many reasons why this might be, for example when they are producing antibodies in response to an infection. Avezov and colleagues hypothesized that stressing the ER might lead to protein misfolding and aggregation by diminishing its ability to function correctly, leading to increased aggregation. “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,” Avezov commented.

One of the factors that has previous hindered this field of research has been the inability to visualise these processes in live cells. Working with teams from Pennsylvania State University and the University of Algarve, the team developed a technique that allows them to detect protein misfolding in live cells. Their method relies on measuring light patterns of a glowing chemical over a scale of nanoseconds—one billionth of a second.

Using this purpose-developed optical single-cell protein aggregate probing approach the investigators were surprised to discover that in fact, stressing the ER did not promote or support protein aggregation, rather, it had the opposite effect. “Strikingly, ER stress, induced by N-glycosylation or Ca2+ pump inhibitors, triggers an aggregates’ clearance activity,” they wrote. “Pharmacological induction of ER stress does not augment aggregates, but rather stimulate their clearance within hours.” Co-lead author Eduardo Melo, PhD, from the University of Algarve, Portugal, further noted, “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.”

The main component of this clearance mechanism appears to be one of a class of proteins known as heat shock proteins (HSPs), more of which are made when cells are exposed to temperatures above their normal growth temperature, and in response to stress. “We show that this disaggregation activity is catalysed by the stress-responsive ER molecular chaperone—BiP,” the team further stated. “Though one cannot exclude a possibility of additional disaggregases’ involvement, the BiP system appears the only ER-resident molecular machine with such a potential.”

Avezov speculates that their findings might help to explain one of the more unusual observations within the field of dementia research. “There have been some studies recently of people in Scandinavian countries who regularly use saunas, suggesting that they may be at lower risk of developing dementia. One possible explanation for this is that this mild stress triggers a higher activity of HSPs, helping correct tangled proteins.”