Cells are often exposed to stressful conditions that can be life-threatening such as high temperatures or toxins. Fortunately, human cells are masters of stress management with a powerful response program: they cease to grow, produce stress-protective factors, and form large structures, which are called stress granules.
Scientists at the Biotechnology Center (BIOTEC) of the TU Dresden and the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), together with partners in Heidelberg and St Louis, USA, have investigated how these mysterious structures assemble and dissolve, and what may cause their transition into a pathological state as observed in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
The results of the study have been published in the journal of Cell.
ALS is a hitherto incurable disease of the central nervous system in which the motor neurons -- nerve cells responsible for the muscles movement -- gradually die.
Stress granules are formed in the cytoplasm of the cell and assemble from a large number of macromolecular components such as messenger RNAs and RNA-binding proteins.
Stress granules usually disassemble when the stress subsides, a process that is promoted by the dynamic nature of stress granules. However, a hallmark of ALS is the presence of non-dynamic, persistent forms of stress granules.
"In ALS, patients suffer from muscle weakness and paralysis. Stress granule-containing motor neurons slowly degenerate, causing a progressive loss of motor functions," said Dr Titus Franzmann, one of the senior authors of the publication.
"We need to better understand the complex biology of stress granules in order to design and develop future therapeutic strategies that counteract the course of the disease. But the complex environment of the cells within an orgsm makes this difficult," added Dr Franzmann.
In order to systematically test their hypotheses about the assembly of stress granules and the pathology causing molecular changes, the scientists developed a controlled environment using an in vitro system with purified components that allowed the recreation of stress granules in a test tube.
They observed stress granule assembly step by step and characterized the critical factors underlying their dynamics.
"Stress granules have a very complex structure. Nevertheless, their formation depends primarily on the behaviour of a single protein - the RNA-binding protein G3BP. This protein undergoes a critical structural change: Under non-stress conditions, G3BP adopts a compact state that does not allow stress granules to assemble," said Dr Jordina Guillen-Boixet, one of the first authors of the study.
"But under stress, RNA molecules bind to G3BP allowing multiple interactions that promote the assembly of dynamic stress granules. The subsequent transition from dynamic into a non-dynamic state, which may be caused for example by prolonged stress, may trigger the death of the motor neurons, as we can observe in the disease ALS," added Guillen-Boixet.
The research project was initiated in 2015 and led by the Alberti research group at TU Dresden's BIOTEC.
The close co-operation of 23 scientists from the TU Dresden, the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, the European Molecular Biology Laboratory in Heidelberg and the Washington University in St. Louis (USA) was central for the success of the project.
"There is a number of remaining questions. Our experimental system at BIOTEC is now available for further testing and will be central to developing new diagnostics and therapeutics to combat neurodegenerative diseases such as ALS," said Prof Simon Alberti.
( With inputs from ANI )