By Bhanu Sontela
Stress granules, which were previously believed to encourage detrimental protein accumulation, may offer protection against neurodegenerative illnesses, including frontotemporal dementia and ALS, according to research from St. Jude Children's Research Hospital and Washington University in St. Louis.
This discovery disproves previous theories that stress granules promote the accumulation of harmful protein aggregation connected to these conditions. Rather, the research indicates that stress granules may be essential in halting the development of harmful fibrils within cells.
“It’s important to know whether stress granules are crucibles for fibril formation or protective,” the study’s co-corresponding author, Dr. Tanja Mittag, said in an article for St. Jude Hospital. “This information will aid in deciding how to develop potential treatments against a whole spectrum of neurodegenerative diseases.”
Previously, researchers thought that the aberrant protein fibers seen in conditions like frontotemporal dementia and ALS might have their origins in stress granules, which are cellular structures that develop in reaction to stress. The latest study demonstrates that although these fibrils can start to form on the surface of stress granules, the growth of the fibrils is actually inhibited by their internal environment. Moreover, disease-associated genetic alterations decrease stress granule stability, increasing the likelihood of fibril formation. On the other hand, mutations that fortify stress granules aid in halting detrimental aggregation.
Rohit Pappu, PhD, co-corresponding author and Director of the Center for Biomolecular Condensates at Washington University in St. Louis, explains the results of this study and its implications.
“This work, anchored in principles of physical chemistry, shows two things: Condensates are kinetically accessible thermodynamic ground states that detour proteins from the slow-growing, pathological fibrillar solids. And the interactions that drive condensation versus fibril formation were separable, which augurs well for therapeutic interventions that enhance the metastability of condensates,” Dr. Pappu said.
The researchers intend to investigate the potential applications of these discoveries in the development of treatments that fortify stress granules and stop the formation of detrimental fibrils in cell and animal models.
If successful, the research could change how neurodegenerative illnesses are treated by strengthening the cell's defenses instead of just focusing on harmful protein aggregation.
