Chronic diseases such as type 2 diabetes and inflammatory disorders significantly impact global health. They account for a large number of health-related complications and mortalities across the world, causing considerable physical and financial strain. Furthermore, the prevalence of these diseases is on the rise.
Finding effective treatments for chronic diseases has been a challenge due to the lack of a single identifiable cause, such as a specific gene mutation. However, a new study led by Richard Young from the Whitehead Institute, recently published in the journal Cell, suggests that many chronic diseases may share a common factor: decreased protein mobility. This implies that when cells are in a chronic disease state, roughly half of all active proteins slow down, affecting their functions. This discovery highlights protein mobility as a potential therapeutic target for chronic diseases.
In the study, Young’s team, including postdoc Alessandra Dall’Agnese and other colleagues, discovered this common protein mobility issue, which they refer to as proteolethargy. They explain its cause, how it leads to cell dysfunction, and propose a new treatment approach for chronic diseases.
Dall’Agnese expresses hope that this discovery could lead to a new category of drugs that enhance protein mobility, potentially benefiting patients with various diseases sharing this common factor.
To understand how decreased protein mobility can cause cell dysfunction, Dall’Agnese explains that each cell can be thought of as a small city, with proteins acting as the workforce. When protein movement slows down, similar to a traffic jam in a city, all operations in the cell are affected, mirroring the widespread issues seen in chronic diseases.
The team first suspected a protein mobility issue in chronic diseases while studying the changes in insulin receptors in diabetic patients. This led them to investigate a range of proteins involved in diverse cellular functions. They found that most of these proteins displayed reduced mobility in disease-afflicted cells, linking protein slowdown to disease pathology.
The researchers then set out to identify what was causing the proteins to slow down. They found that high levels of reactive oxygen species (ROS), molecules that can interfere with other molecules and their chemical reactions, were to blame for the protein mobility defect.
Not all proteins, however, slowed down in the presence of ROS. The only exception in their study was a protein that lacked cysteines, a type of amino acid susceptible to interference from ROS. When ROS causes cysteines from two proteins to bond, it slows down the proteins, explaining the reduced mobility.
These findings suggest that decreased protein mobility due to oxidative stress could be a major factor behind the symptoms of chronic diseases. This is promising for the development of therapies to restore protein mobility. The team found that treating cells with an antioxidant drug, N-acetyl cysteine, partially restored protein mobility.
Young and his team are now focusing on finding drugs that can efficiently reduce ROS and restore protein mobility. They are also investigating other diseases that may involve protein mobility, and exploring the role of reduced protein mobility in aging.
Young expresses hope that the discovery of proteolethargy and its potential contribution to chronic diseases will revolutionize the development of treatments effective across various chronic conditions.
