New Insights into Stress Granules and Their Role in Neurodegenerative Diseases

Recent research conducted by scientists from St. Jude Children's Research Hospital and Washington University in St. Louis has provided significant mechanistic understanding of how biomolecular condensates, specifically stress granules, influence neurodegenerative disease pathology. Published in the journal Molecular Cell, the study explores the interactions that determine whether proteins form condensates or amyloid fibrils, the latter being closely associated with neurodegenerative conditions such as ALS and FTD. Stress granules are dynamic biomolecular assemblies that form in cells under stress conditions to temporarily halt essential processes like protein synthesis. These granules are considered metastable and have been implicated as potential drivers of disease, with previous theories suggesting they might serve as sites for amyloid fibril formation.

The researchers demonstrated that driver proteins tend to form fibrils as the stable end state, while condensates are metastable states that can act as sinks. Crucially, disease-associated mutations weaken the metastability of these condensates, promoting fibril formation — an abnormal process linked to neurodegeneration. Interestingly, the study revealed that although fibrils can initiate from surfaces of stress granules, the interior of these condensates actually suppresses fibril growth, suggesting stress granules might serve a protective role rather than being the origin of toxic fibrils.

This discovery challenges previous assumptions about stress granules serving as a crucible for fibril formation and opens new avenues for therapeutic interventions. Enhancing the stability of stress granules could potentially prevent or slow fibril development, offering a promising strategy to combat neurodegenerative diseases. The study was led by Dr. Tanja Mittag and Dr. Rohit Pappu, highlighting that physical chemistry principles underpin the behavior of these biomolecular condensates and their impact on disease processes.