Chronic illnesses like diabetes are increasingly prevalent, posing significant challenges and costs for treatment. Researchers have identified a potential unifying factor underlying these varied diseases: a phenomenon known as proteolethargy, which refers to decreased protein movement in cells, particularly when oxidative stress is present.
Chronic conditions such as type 2 diabetes and inflammatory diseases greatly affect global health. They contribute significantly to illness and mortality, burdening both individuals and economies, with their prevalence continually on the rise.
Diagnosing and treating chronic diseases has been difficult due to their complex nature, which typically does not involve a single identifiable cause, such as a particular gene mutation. However, research led by Richard Young from the Whitehead Institute, published in the journal Cell on November 27, reveals that many chronic illnesses may share a critical underlying issue: the slowing of proteins within cells. This reduced protein mobility means that about half of all active proteins in a diseased state move more slowly compared to their state in healthy cells, restricting their functional capabilities. The researchers suggest that this protein mobility issue may significantly contribute to decreased cellular function associated with chronic diseases, presenting a promising avenue for therapeutic intervention.
In their study, Young and his team, including postdoc Alessandra Dall’Agnese, graduate students Shannon Moreno and Ming Zheng, and research scientist Tong Ihn Lee, provide insights into this shared mobility issue—termed proteolethargy. They explore the causes of this issue and its implications for cellular dysfunction while proposing a novel therapeutic strategy for treating chronic conditions.
“I’m thrilled about the potential impact of this research on patients,” Dall’Agnese states. “My aspiration is that it could pave the way for a new class of medications aimed at restoring protein mobility, potentially benefiting individuals suffering from various diseases that all share this mechanism.”
“This research represents a collaborative, interdisciplinary initiative that combined the expertise of biologists, physicists, chemists, computer scientists, and physician-scientists,” Lee notes. “This diverse expertise is a great asset of the Young lab. By examining the problem from multiple perspectives, we gained deeper insights into how this mechanism operates and how it might reshape our understanding of chronic disease pathology.”
Commuter delays hinder cellular functions
So, how does a slowdown in protein movement within cells lead to widespread cellular dysfunction? Dall’Agnese likens cells to small cities, where proteins act as the workforce essential to keeping operations running smoothly. These proteins must navigate through congested cellular environments, moving from their production sites to their functional locations. Faster mobility equates to increased productivity. Visualize a city grappling with heavy traffic: businesses may open late, deliveries may become delayed, and meetings might be postponed. Essentially, this disruption leads to a slowdown in city operations.
Similarly, in cells experiencing reduced protein mobility, overall operations suffer a delay. Normally, proteins actively engage with other molecules until they find their target. The reduced speed of protein movement limits their interactions, substantially decreasing their ability to perform their functions. Young and his team discovered that such slowdowns correspond to measurable declines in the proteins’ functional outcomes. When numerous proteins fail to execute their roles effectively, cells encounter various issues, mirroring abnormalities seen in chronic diseases.
Identifying the issue with protein mobility
Young’s research group first considered the hypothesis of protein mobility impairment in diseased cells after observing alterations in the insulin receptor, a signaling protein that responds to insulin and enables cells to absorb sugar from the bloodstream. In individuals with diabetes, cells become less sensitive to insulin—termed insulin resistance—leading to elevated blood sugar levels. A prior study published in Nature Communications in 2022 indicated that insulin receptor mobility may be pertinent to diabetes.
Acknowledging the numerous cellular functions affected by diabetes, the researchers proposed that flawed protein mobility might influence many cellular proteins. To explore this, they assessed proteins related to various functions, including MED1 (in gene expression), HP1α (in gene silencing), FIB1 (in ribosome production), and SRSF2 (in mRNA splicing). Employing single-molecule tracking and other techniques, they quantified how each protein moves in healthy and diseased cells. Remarkably, all but one of the proteins exhibited decreased mobility (approximately 20-35%) in disease-affected cells.
“I’m excited that we successfully applied physics-based insights and methodologies—traditionally used to study single-molecule processes like gene transcription in healthy cells—to a disease context, uncovering unexpected disease mechanisms,” Zheng remarked. “This study illustrates how the random movement of proteins within cells correlates with disease pathology.”
Moreno added, “In educational settings, we often focus on structural changes in proteins or gene sequences when exploring disease causes. We have illustrated here that these are not the only factors to consider. Only looking at a static snapshot of a protein or cell can lead to missing dynamic changes that occur when molecules are active.”
Stuck in traffic, can’t navigate the cell
The researchers’ next step was to identify the causes for the slowdown in protein mobility. They speculated that the problem could stem from increased levels of reactive oxygen species (ROS) in the cells, which can disrupt molecular interactions. Various triggers associated with chronic diseases—such as elevated sugar or fat levels, certain toxins, and inflammatory signals—can escalate ROS levels, creating oxidative stress. By measuring protein mobility in cells with heightened ROS levels but not exhibiting disease characteristics, they observed similar mobility impairments, suggesting that oxidative stress is implicated in the protein mobility problem.
Lastly, they sought to understand why some proteins experience reduced motion in the presence of ROS while others do not. SRSF2 was the only protein unaffected in their tests, primarily due to its lack of cysteines—an amino acid often found on protein surfaces. Cysteines are particularly prone to reactions with ROS, leading them to bond with other cysteines, which, in turn, restricts mobility among protein pairs. Approximately half of the proteins in our body carry these surface cysteines, meaning this mobility defect can significantly impact multiple cellular pathways. This is crucial considering the variety of dysfunctions that arise in cells affected by chronic diseases: these include disruptions in cell signaling, metabolism, gene expression, and more—all of which rely on the proper functioning of proteins, including those studied by the researchers. Young’s team undertook additional experiments confirming that reduced protein mobility indeed limits a protein’s performance. For instance, when the mobility of an insulin receptor decreases, its efficiency in activating IRS1, a molecule it typically phosphorylates, declines.
Translating insights into disease treatment
The revelation that decreased protein mobility due to oxidative stress could drive many chronic disease symptoms opens avenues for developing therapies to restore this mobility. During their experiments, the researchers treated cells with an antioxidant drug—N-acetylcysteine—aimed at reducing ROS levels and observed a partial restoration of protein mobility.
The research team intends to pursue several follow-up studies, including efforts to find drugs that efficiently lower ROS levels and enhance protein mobility. They have created an assay to screen potential drugs by comparing their effects on a biomarker with surface cysteines against another without. The researchers are also investigating other diseases that may involve protein mobility issues and considering how reduced protein mobility might contribute to aging processes.
“The intricate biology of chronic diseases has presented significant challenges in formulating effective therapeutic strategies,” remarks Young, a professor of biology at the Massachusetts Institute of Technology. “Discovering that various disease-associated stimuli induce a common phenomenon, proteolethargy, which might underlie much of the regulatory dysfunction seen in chronic diseases, could be a transformative step toward creating drugs that address a wide range of these conditions.”
