St. Jude Children's Research Hospital scientists have discovered a key mechanism for amyotrophic lateral sclerosis (ALS) and related degenerative diseases. The study is published in the journal Cell, providing a new therapeutic approach for the devastating diseases.
Under stress conditions, cells can form a short-lived compartments—stress granules, that assemble when cells need to and quickly disperse until the task is completed. Stress granule is also closely related to degenerative diseases, such as ALS, whose gene encoding the protein component of mutation often occurs in the disease. These proteins of stress granules can accumulate into integrated amyloid fibers in nerve and muscle cells of of patients with ALS, frontotemporal dementia (FTD) and inclusion body myopathy (IBM). But the unifying mechanism was still a mystery.
"This study provides the mechanism that links stress granules, toxic fibrils and disease," said co-corresponding author J. Paul Taylor, M.D., Ph.D., chair of the St. Jude Department of Cell and Molecular Biology. "In addition to advancing our understanding of fundamental cell biology, the results have spurred interest in developing drugs that target the stress granule assembly process."
"The disordered segment or tail of hnRNPA1, a protein that is sometimes mutated in ALS and related disorders, is the key to unlocking the connection among stress granules, fibrils and disease," said co-corresponding author Tanja Mittag, Ph.D., an assistant member of the St. Jude Department of Structural Biology. " hnRNPA1 is an RNA-binding protein involved in stress granule formation."
Proteins are long strings of amino acids that often need for specific 3D structure folded. If one end of hnRNPA1 is not folded, it can form a variety of conformations. The study has shown that under certain conditions (temperature, salt concentration and protein-related), the disordered tail of hnRNPA1 will prompt the protein to condense into droplets by liquid phase separation. Such droplets have similar performance to stress granules, including the integration and growth capacity.
So far, it is not believed that the liquid phase separation process plays a role in normal cell function, and this study was the first to link the process with stress particle assembly.
"It is amazing to find out that proteins like hnRNPA1 have appeared in nature to mediate liquid phase separation under normal physiological conditions," Mittag said. "The long disordered tails in these proteins enable membrane-less compartmentalization in cells. In addition, liquid phase separation is probably important for a whole range of fundamental biological processes."
The researchers found that if hnRNPA1 with mutations in the disordered tail is concentrated into droplets by phase separation, the protein will immediately form amyloid fibers. However, if the mutant protein did not concentrated into droplets, toxic fibers will not form.
The neuropathy of patients with ALS, FTD and IBM can affect walking, swallowing and breathing, but there is a lack of effective treatment. The study has shown that the assembly process of stress granules as a target for treatment is promising.
Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell