Magdalena Gotz and her team evaluated in neurons the notion of similarity of the centrosome in all cells, and their developmental precursors, so-called neuronal stem cells. “There is so much we don’t yet know about these cells, including how the centrosomes of neurons compare to those of neural stem cells and other cell types,” Götz says. Their subsequent discoveries now fundamentally challenge the assumption that all centrosomes are created equal. Centrosomes are in fact not, “one type fits all.”
In close collaboration with the Helmholtz Munich Proteomic Core Facility led by Stefanie Hauck, the researchers found that the composition of proteins in centrosomes differs profoundly depending on the cell type. “We were surprised not only by the unexpectedly high degree of heterogeneity of the centrosomes but also by the discovery of many unexpected proteins associated with them – for example, RNA-binding proteins and even proteins responsible for splicing (the processing of RNA), which normally takes place in the nucleus,” Götz explains: The location of centrosome-associated proteins is crucial for disease.
The scientists discovered that a specific protein (the ubiquitously expressed splicing protein PRPF6) is enriched at the centrosome in neural stem cells, but not in neurons. A mutation of the protein found in patients with brain malformation periventricular heterotopia also leads to a similar phenotype in animal models. Magdalena Götz concludes, “This means that the location of a protein is crucial for a disease. With our centrosome analysis, we now have an important resource to test further associations with neuronal diseases. In particular, our research can explain for the first time why a protein that is present in all cells, after mutation, causes a phenotype only in the brain, but not in other organs. This will allow further insights into disease mechanisms – and thus get one step closer to their treatment.”