How cells beat the ‘fried-egg syndrome’

22 January 2020

In brain diseases such as Huntington’s and Alzheimer’s Disease, abnormal accumulations of protein aggregates or clumps are thought to be a central feature of these diseases.

Cells, enclosed by a fatty membrane contain many proteins, which do the ‘work’ of the cell. They catalyse chemical reactions, send messages to activate or inhibit certain functions within the cell, or simply provide structural support for cell movement and division. Under the microscope, you can see that it is definitely a tight squeeze within the cell, packing in a lot of proteins and organelles. How is this possible? The ability of proteins to exist in soluble and solid ‘aggregated’ states, may provide a clue. 

Professor Danny Hatters and his group at the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences and Bio21 Institute show in work published today in PNAS that the body’s cells have a way of regulating the solubility of their proteins which are densely packed inside the cell; floating or actively moving within the cell’s liquid ‘cytosol’. 

The research involved a productive collaboration with Bio21 teams, as well as international researchers from the University of Cambridge.

"My ongoing collaboration with Gavin Reid was essential for the proteomics approaches we used, which included close involvement of Shuai Nie from the Proteomics and Mass Spectrometry facility. Working with David Ascher and Douglas Pires' bioinformatics approaches also leant depth to the work and analyses. We also collaborated with Michele Vendruscolo and his postdoc  Giulia Vecchi at Cambridge University (UK), who helped develop some of the thinking in the context of their prior work on proteome supersaturation." says Professor Hatters. "The quality and depth of the study was underpinned by the collaborations, and particularly the access to the outstanding proteomics platform technology faciliy at Bio21," says Professor Hatters. 

“Balance is everything in life and the cell seeks to strike a balance between soluble and aggregated proteins depending on the type of stress they experience,” explains Professor Hatters.

“Normally proteins within the cell can exist in a soluble, or aggregated solid form and switch between these states. However, sometimes aggregates form abnormally. This process is called ‘protein misfolding.’”

A good analogy of misfolding is when you heat an egg in a pan.  Within a few seconds the gelatinous clear egg white, which is full of protein, hardens into an opaque ‘egg white’. The heat has denatured the egg protein ‘ovalbumin’, resulting in a change in structure. If you were to observe these changes at the molecular level, you would see that the egg white protein, has changed its conformation and stuck to other ovalbumin molecules.

This change in the protein from a solution to a solid form is called aggregation. When this happens abnormally in brain cells, it is thought to be the cause of a number of neurodegenerative brain diseases, such as Huntington’s Disease, Alzheimer’s and Parkinson’s Disease.

Soluble proteins are easily transported through nuclear pores, or incorporated into signalling pathways, where they can do work.

If such proteins become abnormally aggregated, they can no longer function properly. Their unwieldy shapes clog up channels and pores and generally get in the way of the business of running a healthy cell.

It has been hypothesized that the abnormal aggregates arise in large part due to a failure of quality control systems that normally clear incorrectly folded and unwanted proteins that are prone to aggregating. It has also been hypothesized that some proteins, such as those seen aggregating in disease, might be particularly prone to aggregating when protein quality control systems fail. Other than those seen in disease, a comprehensive understanding of which proteins are vulnerable is not known.

Hatters is interested in these ‘quality control mechanisms’ within the body’s cells. Understanding this in a fundamental way could shed clues to how disease arises in the brain when the quality control systems fail to control aggregation.

Danny wished to measure the extent of abnormal aggregation in the context of the normal balance of soluble and aggregated protein, when protein quality control systems are stressed.

Like products moving along a factory conveyor belt, the cell’s proteins are assessed for quality at specific ‘checkpoints.’ By altering or inhibiting these checkpoints within the cell’s quality control system, Hatters hoped to understand how this may result in abnormal protein aggregation. 

In order to measure this, Hatters used cutting edge quantitative proteomics at Bio21 combined with ultracentrifugation and a cell culture model to determine which proteins became more or less soluble.

Hatters was surprised to see that the cell displayed strong resilience against this kind of assault.

“We saw that proteins inside cells were changing between a soluble and aggregated state in an orchestrated and specific way, depending on the type of stress that they were experiencing. They were actively compensating for the stress experienced, working to gain a balanced state.”

In terms of human health, stresses that our body’s cells experience may be due to heritable factors, such as mutations that cause disease, or environmental factors, for example, poor nutrition, smoking and excessive alcohol consumption.

“This compensation by the cell may explain why many diseases appear later in life, when the body’s quality control systems start to fail,” says Hatters.

Hatters’ research sheds light on this process, showing that cells seem to be much more resilient against stress factors in their environment than first thought and have robust mechanisms to prevent systems from going out of kilter.

By florienne.loder [at] (subject: Fried-Egg%20Syndrome%20-%20Query) (Florienne Loder)
Communications and Engagement Advisor
Bio21 Institute