Stress granules play a protective role against neurodegenerative disease

Scientists from the research hospital of St. Jude Children and Washington University in St. Louis report a mechanistic insight into the role of biomolecular condensation in the development of neurodegenerative disease. Cooperation, published studies, focused on interactions that drive the formation of condensates compared to the formation of amyloid fibers and the way they relate to stress granules. Stress granules are biomolecular condensans that arise in cell stress conditions and were previously involved as amotrophic side sclerosis (ALS), frontal -protective dementia (FTD) and other neurodegenerative diseases.

Scientists have shown that fibrils are globally stable driver proteins, while condensations are metastabilic sinks. They also showed that the disease -related mutations reduce condensate metastabism, thus increasing the creation of fibers, a pathological feature of key neurodegenerative diseases. Earlier, it was suggested that amyloid fibrils formed by granular proteins resemble structures formed in other neurodegenerative disorders, they come from stress granules. However, scientists have shown that although the formation of fibrils can be initiated on the surfaces of condensates, the interior of condensates actually suppress fibers. This means that condensations are not the keys of ALS or FTD. Mutations that stabilize stress granules have reversed the influence of mutations that cause disease in test tubes and cells, indicating the protective role of stress granules in neurodegenerative diseases.

It is important to know if stress granules are the keys to create fibers or protective. This information will help you decide on how to develop potential treatment in relation to the entire spectrum of neurodegenerative diseases. “

Dr. Tanja Mittag, author of Study, responding

Mittag led work with a interdependent author, Rohit PAPPU, gene K. Beare-Distinguished Professor of Biomedical Engineering and director of the Center for Biomolecular Condensates at Washington University in St. Louis’s McKelvey School of Engineering, as a successful St. Jude Research Collaborative Collaboration Collaboration Collaborative.

“This work, anchored in the principles of physical chemistry, shows two things: condensations are kinetically available thermodynamic ground. condensates.

The fibrils of the disease are formed with or without stress granules

In stress conditions, such as heat, cells form stress granules to temporarily stop energy -consuming processes, such as protein production. It is similar to the ship leaving the sails during a storm. When the stress disappears, the granules decompose and normal processes resume. Pathogenic mutations in the key proteins of stress granules, such as HNRNPA1, extended the life of stress granules and drive the creation of insoluble fabric threads that accumulate in time, causing neurodegeneration.

Mittag, PAPPU and their teams examined HNRNPA1 to better understand the relationship between stress granules and the formation of fibers. They discovered that the mutations related to the disease drive proteins from the interior of the condensate faster than “wild” proteins, thus enabling the formation of fibers when they leave the condensate.

“We found that condensations are” metastabal “in relation to fibers, which means that they act as a sink for soluble proteins,” he explained that the author of Fatima Zaidi Fatima Zaidi, St. Jude Department of Strutural Biology. “In the end, however, proteins are pulled out of condensate, creating globally stable fibers.”

The authors also showed that while the fibers begin to grow on the surfaces of condensate, the proteins eventually joined the fibers resulting from the outside, and not from the inside of the condensate. Fibrils can also form with a complete lack of condenses.

Based on these basic discoveries made jointly in the Mittag and PApp laboratories, scientists designed protein mutants that can suppress the process of creating fibers in favor of creating condensate. Interestingly, this approach also restored the dynamics of normal stress granules in cells wearing ALS mutations.

“In total, it suggests that stress granules should be seen not as a melting pot, but rather a potential protective barrier for diseases,” said Dr. Tapojoti Das, Department of St. Jude Department of Structural Biology.

These discoveries illuminate the role of stress granules in the pathogenic formation of fibrils and constitute an important basis for the study of new therapeutic approaches of neurodegenerative diseases.

Authors and financing

Other authors of the study are Mina Farag and Kisten Ruff, Washington University in St. Louis; Tharaun Selvam Mahendran, Aura Singh and Priya Banner, State University of New York in Buffalo; and Xinrui GUI, James Messing and J. Paul Taylor, St. Jude.

The study was supported by the National Institutes of Health (R01ns121114, R35ns097974, R35GM138186), Collaborative Research St. Jude in the field of biology and biophysics of RNP granules, Air Force of Scientific Research (FA9550-20-1-1-0241). Lebanese Syrian charity organizations (ALSAC), Organization of obtaining funds and awareness of St. Jude.