Researchers from St. Jude Children’s Research Hospital and Washington University in St. Louis have shared mechanistic insights regarding the function of biomolecular condensation in the onset of neurodegenerative disorders. The collaborative investigation, published in Molecular Cell, concentrated on the interactions that promote the creation of condensates versus the development of amyloid fibrils and how these are interconnected with stress granules. Stress granules are biomolecular condensates that arise in situations of cellular stress and have been previously linked as contributors to amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and various other neurodegenerative conditions.
The team revealed that fibrils represent the globally stable states of driver proteins, while condensates serve as metastable sinks. They also demonstrated that mutations linked to diseases reduce the metastability of condensates, thus promoting fibril creation, which is the pathological hallmark of several significant neurodegenerative disorders.
Amyloid fibrils generated by stress granule proteins, resembling structures observed in other neurodegenerative conditions, have been previously posited to initiate within stress granules. Yet, the researchers established that although fibril formation may start on the surfaces of condensates, the interiors of these condensates actually inhibit fibril formation. This indicates that these condensates are not necessarily promoters of ALS or FTD. Mutations that stabilize stress granules could negate the effects of disease-related mutations in test tubes and cells, suggesting a protective function of stress granules in neurodegenerative diseases.
“Understanding whether stress granules serve as vessels for fibril creation or as protective mechanisms is crucial,” stated the study’s co-corresponding author Tanja Mittag, from the St. Jude Department of Structural Biology. “This knowledge will help inform strategies for developing potential treatments against a wide array of neurodegenerative diseases.”
Mittag led the study in conjunction with co-corresponding author Rohit Pappu, the Gene K. Beare Distinguished Professor of Biomedical Engineering and director of the Center for Biomolecular Condensates at Washington University in St. Louis’ McKelvey School of Engineering, as part of the successful St. Jude Research Collaborative on the Biology and Biophysics of RNP Granules.
“This research, grounded in principles of physical chemistry, reveals two key elements: Condensates are kinetically accessible thermodynamic ground states that divert proteins from the slow-growing, pathological fibrillar solids. Moreover, the interactions that facilitate condensation versus fibril creation were distinct, which is promising for therapeutic strategies aimed at enhancing the metastability of condensates,” Pappu stated.
Disease fibrils form with or without stress granules
In times of stress such as elevated temperatures, cells generate stress granules to temporarily pause energy-demanding processes like protein synthesis. This is similar to a ship lowering its sails during a tempest. Once the stress abates, the granules dismantle, and regular activities resume. Pathogenic mutations in vital stress granule proteins like hNRNPA1 prolong the existence of stress granules and trigger the development of insoluble fibril strands, which accumulate over time, leading to neurodegeneration.
Mittag, Pappu, and their teams studied hNRNPA1 to further understand the connection between stress granules and fibril formation. They discovered that disease-related mutations drive proteins away from the interiors of condensates more rapidly than the “wild-type” proteins, thus facilitating fibril formation as they exit the condensate.
“We identified that condensates are ‘metastable’ concerning fibrils, meaning they function as a reservoir for soluble proteins,” clarified co-first author Fatima Zaidi from the St. Jude Department of Structural Biology. “However, over time, proteins are attracted out of the condensate to form the globally stable fibrils.”
The authors additionally revealed that while fibrils begin to grow on the surfaces of condensates, the proteins that ultimately comprise these fibrils originate from outside, not from within the condensates. Fibrils may also form completely independently of condensates.
Expanding on these fundamental insights gained collaboratively in the Mittag and Pappu laboratories, the researchers engineered protein mutants that could inhibit the process of fibril formation, favoring condensate formation instead. Remarkably, this tactic restored normal stress granule dynamics in cells bearing mutations linked to ALS.
“This collectively suggests that stress granules should not be viewed merely as vessels, but rather as potential protective barriers against disease,” noted co-first author Tapojyoti Das from the St. Jude Department of Structural Biology.
These findings clarify the function of stress granules in the formation of pathogenic fibrils and lay an essential groundwork for exploring innovative therapeutic methods for neurodegenerative diseases.
Initially published on the St. Jude Research News and the McKelvey School of Engineering websites.
Das T, Zaidi F, Farag M, Ruff KM, Mahendran TS, Singh A, Gui X, Messing J, Taylor JP, Banerjee PR, Pappu RV, Mittag T. Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation. Molecular Cell. online May 28. DOI: https://10.1016/j.molcel.2025.05.011
The investigation received support from the National Institutes of Health (R01NS121114, R35NS097974, R35GM138186), the St. Jude Research Collaborative on the Biology and Biophysics of RNP granules, the Air Force Office of Scientific Research (FA9550-20-1-0241), the National Cancer Institute (P30 CA021765), and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
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