Research reveals protein mobility defects are a key factor in chronic diseases

Chronic diseases such as type 2 diabetes and inflammatory diseases have a significant impact on humanity. They are a major cause of disease burden and mortality worldwide, are physically and economically burdensome, and the number of people affected by such diseases continues to grow.

Treating chronic diseases has proven difficult because they do not have one simple cause, such as a single gene. mutationmay be eligible for treatment. At least, that's how it seemed to scientists. However, a study by Richard Young, a member of the Whitehead Institute, and his colleagues was published in the journal. cell Researchers on November 27 revealed that many chronic diseases have a common denominator that may be driving their dysfunction: reduced protein mobility. What this means is that when a cell is in a chronic disease state, about half of the active proteins in the cell slow down and protein function is reduced. The researchers' findings suggest that protein mobility is central to the decline in cellular function in chronic diseases and may represent a promising therapeutic target.

In this paper, Young and his lab colleagues, including postdoc Alessandra D'Alagnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ying Li, describe how they They describe the discovery of this common movement defect, which they call oresathy. Explain the cause of the defect and how it leads to cell dysfunction. We propose new therapeutic hypotheses to treat chronic diseases.

“I'm very excited about what this study means for patients,” says Dall'Agnese. “My hope is that this will lead to a new class of drugs that restore protein mobility and can help people with many different diseases that have this mechanism as a common feature.”

“This research was an interdisciplinary collaboration, bringing together biologists, physicists, chemists, computer scientists, and physician-scientists,” Lee said. “That combination of expertise is a strength of the Young lab. Studying a problem from different perspectives can change our understanding of how this mechanism works and the pathology of chronic diseases. It really helped me think about what I could do.”

Work in the cell comes to a halt due to commute delays

How does moving proteins more slowly through cells cause widespread and significant cellular dysfunction? Dall'Agnese explains that every cell is like a small city, and that all proteins Explain that they are the workers who keep things moving. Proteins must travel in dense traffic within cells from where they are made to where they work. The faster you commute, the more work you can get done. Now, imagine a city where all the roads start to have traffic jams. Stores don't open on time, groceries get stuck in transit, and meetings are postponed. Basically all business in the city will be delayed.

Decreased cellular behavior with reduced protein mobility follows a similar course. Normally, most proteins fly around inside cells, bumping into other molecules to find molecules to work with and interact with. The slower a protein moves, the fewer other molecules it can reach and the less likely it is to be able to do its job. Young et al. found that such a slowdown of the protein led to a measurable reduction in the protein's functional output. When many proteins are unable to finish their work in time, cells begin to experience various problems, as is known to occur in chronic diseases.

Discovering protein mobility problems

After observing changes in the behavior of insulin receptors, signaling proteins that allow cells to take up sugar from the blood in response to the presence of insulin, Young and his colleagues found that cells with chronic diseases have problems with protein mobility. My first suspicion was that there was. in person with diabetescells become less responsive to insulin – a condition called insulin resistance – resulting in excess sugar remaining in the blood. In studies published on insulin receptors, nature communications In 2022, Young et al. reported that insulin receptor mobility may be associated with diabetes.

Knowing that many cellular functions change in diabetes, the researchers thought that changes in protein mobility might somehow affect many proteins within the cell. To test this hypothesis, they studied proteins involved in a wide range of cellular functions, including MED1, a protein involved in gene expression. HP1α, a protein involved in gene silencing. FIB1, a protein involved in ribosome production. SRSF2 is a protein involved in messenger RNA splicing. They used single-molecule tracking and other methods to measure how each of these proteins moves within healthy cells and cells in disease states. All but one protein showed reduced mobility (approximately 20–35%) within diseased cells.

“Physics-based insights and methodologies commonly used to understand single-molecule processes such as gene transcription in normal cells can be transferred to disease contexts and used to uncover unanticipated problems. “We're excited to be able to show that we've elucidated the mechanism of the disease,” says Zheng. “This study shows how random walks of proteins within cells are associated with disease pathology.”

Moreno agrees. “While we are taught in school to consider changes in protein structure and DNA sequence when looking for the cause of disease, we have demonstrated that these are not the only contributing factors. When we observe this, we miss discovering changes that only occur when molecules are in motion.”

Can't commute beyond the cell, everything is tied up now

Next, the researchers needed to determine what was slowing down the protein. They suspected that this defect might be related to increased intracellular levels of reactive oxygen species (ROS), molecules that are highly susceptible to interfering with other molecules and their chemical reactions. Many types of triggers associated with chronic diseases, such as increased sugar and fat levels, certain toxins, and inflammatory signals, lead to increased ROS, also known as increased oxidative stress. When the researchers measured protein mobility again in cells that had high levels of ROS but were otherwise free of the disease state, they found comparable mobility defects, indicating that oxidative stress can affect protein mobility. It was suggested that this was the cause of the defect.

The final piece of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only protein unaffected in the experiment, with one clear difference from the other proteins. That is, its surface did not contain cysteine, the amino acid building block of many proteins. Cysteines are particularly susceptible to interference by ROS due to their binding with other cysteines. When this binding occurs between two protein molecules, the binding is slowed down because the two proteins cannot move through the cell as quickly as either protein alone.

Approximately half of the proteins in our cells contain surface cysteines, so defects in the mobility of this single protein can affect many different cellular pathways. This makes sense given the variety of dysfunctions that occur in cells of people with chronic diseases, including dysfunctions in cell signaling, metabolic processes, and gene expression and gene silencing. All of these processes depend on the efficient functioning of proteins, including a variety of proteins that have been studied by researchers. Young et al. conducted several experiments to confirm that reducing protein mobility actually reduces protein function. For example, researchers found that reducing the mobility of the insulin receptor reduces its effect on IRS1, a molecule that normally adds phosphate groups.

From understanding mechanisms to treating diseases

The discovery that reduced protein mobility in the presence of oxidative stress may cause many of the symptoms of chronic disease provides an opportunity to develop treatments that restore protein mobility. I will. During the course of the experiment, the researchers treated the cells with an antioxidant called N-acetylcysteine, a substance that reduces ROS, and found that this partially restored protein mobility.

The researchers are pursuing a variety of follow-up investigations into this work, including searching for drugs that safely and efficiently reduce ROS and restore protein mobility. They developed an assay that can be used to screen drugs to see if they restore protein mobility by comparing the effect of each drug against a simpler drug. biomarker with and without surface cysteine. They are also investigating other diseases that may be associated with protein trafficking and are investigating the role of reduced protein mobility in aging.

“The complexity of chronic disease biology makes it difficult to develop effective treatment hypotheses,” says Young, who is also a professor of biology at the Massachusetts Institute of Technology. “The discovery that stimuli associated with a variety of diseases all induce a common feature called proteoresia, and that this feature may contribute to many of the dysregulations seen in chronic diseases, is an important contribution to drug development. We are working across the spectrum of chronic disease. ”