Nuclear and cytoplasmic phase separation enable novel functions of the SMN complex in RNP homeostasis.
- Principal investigator(s):
- Professor Oliver Gruß
- Institute of Genetics, Rheinische Friedrich-Wilhelms Universität Bonn
- Grant Type:
- Operating Grant
- Start Year:
- 3 years
- Call number:
Professor Oliver Gruß
Professor Gruß is a biochemist by training. He received his Diploma from Regensburg University. After his PhD and habilitation (a formal qualification needed to become a university professor in Germany) in Molecular Cell Biology at the University of Heidelberg and the European Molecular Biology Laboratory, he was appointed Professor of Genetics at the University of Bonn in 2015.
A common feature of all people who live with SMA is that their body cells do not produce enough functional SMN protein. This affects just a few cell types, such as the motoneurons, which cannot function properly without, or too little of it. For the rational design of SMA treatment options, it is key to understand the cellular function of SMN, its regulation and how it is affected in disease.
The inside of cells is full of molecules and therefore crowded, which often hinders their proper function. To overcome this, cells use a process called “phase separation” to bring certain components together in distinct domains and at the same time exclude those that are not needed. This allows the efficient execution of a given task. SMN is part of such domains and this localisation is disturbed in SMA.
With this grant, Professor Gruß and his team will seek to understand how this “separation” influences the function of SMN in known and potential new pathways and how it contributes to the events that lead to SMA.
How will Professor Gruß and his collaborators do this?
It is well established that the SMN complex can “separate” from the cytoplasm and the nucleoplasm to form distinct “sections”, particularly under cellular stress. The team has unravelled signalling cues that control SMN’s phase separation and proposes that separation and its regulation contribute to the function of the SMN complex, either in its established pathway or in novel pathways yet to be discovered.
They will exploit assays to directly visualise SMN’s canonical function in snRNP assembly, as well as a potential novel role in snRNP disassembly both in the nucleus and the cytoplasm. Comparing conditions that allow or preclude signals for SMN to separate will reveal specific functions of SMN’s separation capacity.
In a cellular model that mimics SMA, the team will evaluate if delay or defect in phase separation may contribute to SMN’s malfunction in SMA. This will potentially unravel a novel aspect to understand the molecular basis of SMN’s pathology in the disease.
Why is it interesting to patients?
Phase separation emerges as a general principle to regulate molecular functions under cellular stress conditions. Even though SMN has been known to undergo phase separation for more than 25 years, the impact on its functions is not well understood and underappreciated. Understanding the signals that drive SMN’s phase separation and finding ways to manipulate these with established drugs may enable the development of a novel therapeutic approaches to improve the disease.