Stress Granules · Using Reconstituted Stress Granules to Gain Insight into the Molecular Pathology of Neurodegenerative Diseases

Using Reconstituted Stress Granules to Gain Insight into the Molecular Pathology of Neurodegenerative Diseases

Membrane-less compartments were recently discovered as an organising principle inside the cell. They were shown to form by phase separation, a mechanism well understood by physics but new to biology. Since this field of research is still young, the biochemistry and physiology of membrane-less compartments is not well studied. Importantly, membrane-less compartments were implicated in many diseases. Therefore, a better understanding of their biology and pathology could open up new avenues for treatment options. The overall objective of the project was to gain a deeper mechanistic insight into two different types of membrane-less compartments: cytoplasmic stress granules (SGs) and nuclear transcription factor (TF) condensates. The goal was to study their properties in vitro and to understand what functional consequences their manipulation has in vivo. I reconstituted minimal SGs in the test tube and studied the recruitment of different components that can also be found inside cellular SGs. I discovered that protein-protein interactions play a smaller role than previously thought and that RNA-protein interactions are likely to be the determining factor for localisation. Furthermore, SG properties can be affected by targeting the recruited proteins with small molecules rather than the components essential for their formation. This is important knowledge in order to design drugs that delay SG solidification and thus positively affect the onset of neurodegeneration. Furthermore, I also formed TF condensates on DNA. We discovered that a different physical phenomenon leads to the condensation of TFs than to the formation of SGs. We could also explain, for the first time, how TFs can recognise certain functional regions on the DNA and how condensation makes the process of gene activation more robust to varying protein concentrations. This knowledge is essential if we want to control the condensation of TFs and thus gene activation in the future. Possible applications concern treating diseases such as neurodegeneration, cancer, or developmental defects.

Data: CORDIS, © European Union