Do All Chronic Diseases Share a Common Thread?

stethoscope and marker, voice bubble reading chronic diseases

Defined as health conditions lasting for an extended period — typically a year or more — chronic diseases are a leading cause of illness, medical system burden, and death around the globe. From diabetes to heart disease, chronic diseases have a wide array of symptoms, causes, and risk factors. However, recent research published in the journal Cell reveals something surprising: many chronic diseases have a common factor. The research examines the role of reduced protein mobility, which the researchers dubbed “proteolethargy,” in chronic diseases across the medical spectrum.

Linking Protein Mobility and Chronic Diseases

How does reduced protein mobility relate to chronic disease, exactly? The team based their research on the fact that every cell in the human body is, essentially a tiny city. Using the city metaphor, we can think of proteins as the workers who keep everything running, “commuting” through dense traffic in the cell to reach essential molecules. But if those proteins experience a “traffic jam,” or some limitation to their mobility, they inevitably reach fewer molecules. When many proteins experience reduced mobility over time, we experience problems at the cellular level — which is generally what occurs in chronic diseases.

Diabetes: A Case Study in Proteolethargy and Chronic Disease

The research team, led by Whitehead Institute member Richard Young, first suspected that cells affected by chronic disease might have a protein mobility problem after observing changes in the behavior of insulin receptors. In individuals with diabetes, a prime example of a chronic disease, the cells eventually become less responsive to insulin. In research published in Nature Communications in 2022, Young and his colleagues reported that insulin receptor mobility might be relevant to long-term diabetes outlook. They tested this hypothesis by studying a number of proteins, including mediator of RNA polymerase II transcription subunit 1 (MED1), a protein involved in gene expression, and serine/arginine-rich splicing factor 2 (SRSF2), a protein involved in the splicing of messenger RNA.

Linking Oxidative Stress and Proteolethargy

The researchers strongly suspected that diabetes was not the only chronic disease with evidence of protein mobility issues. To explore this, they needed to determine what causes proteins to slow down. They suspected that proteolethargy could be linked to an increase in reactive oxygen species (ROS), molecules that frequently interfere with other molecules throughout the body. An increase in ROS is also known as oxidative stress, and it is characteristic of many types of triggers associated with chronic disease.

To explore the role of oxidative stress, the researchers measured the mobility of the proteins again — this time, in cells that had high levels of ROS and were not otherwise in a disease state. Interestingly, they saw comparable mobility defects. This suggests that oxidative stress could be linked to protein mobility issues. But why? To find out, the team looked to SRSF2, the only protein that was unaffected in the experiments.

SRSF2 differed from the other proteins tested in one way: Its surface did not contain any of the amino acid types known as cysteines. These amino acids are the building blocks of many proteins; unfortunately, they are also quite susceptible to interference from ROS. ROS causes cysteines to bond to other cysteines, creating the “traffic jam” scenario in the cell. In other words, the bonded cysteines cannot move quickly enough through the cell to be effective.

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The research team has numerous other avenues to explore, including the potential for therapies to improve protein mobility in chronic disease cases. For example, a ROS-reducing antioxidant drug partially restored protein mobility in early research.

To study chronic diseases such as diabetes, Scantox Neuro offers an inducible type 2 diabetes mouse model, created through a high-fat diet and the injection of streptozotocin. Typical study readouts are body weight, glucose tolerance and insulin sensitivity, cholesterol, liver and inflammation markers, as well as ROS and many more.

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