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Puzzle around a protein - Researchers from Frankfurt and Ulm provide important insights into the rare PURA Syndrome

26 May 2023. The computational biologist Kathi Zarnack from the Buchmann Institute for Molecular Biosciences and the Institute of Molecular Biosciences at Goethe University investigates what happens in the cells of patients with PURA Syndrome, a genetically determined neurodevelopmental disorder. In a study conducted jointly with Dierk Niessing at the University of Ulm, she has now come a significant step closer to solving the mystery. The study showed that the regulation and quality control of messenger RNAs in the cells were affected. Their findings about molecular and cellular networks have now been published in the journal Nucleic Acids Research and could provide approaches to future therapy studies for the hitherto incurable disease.

The PURA Syndrome is a rare neuronal disorder with severe developmental abnormalities from birth. In addition to learning disabilities and mental developmental delay, the children may suffer from seizures, decreased muscle tone, and problems with feeding and breathing. Since the discovery of PURA Syndrome in 2014, a little over 20 patients have been genetically identified in Germany. At the molecular level, the disease involves a mutation of the PURA gene, which results in reduced levels of the encoded PURA protein. "Although we already had a fairly clear understanding of the structural and molecular properties of the PURA protein," Kathi Zarnack said, "we lacked an understanding of which cellular functions are controlled by PURA." Therefore, the study aimed to identify molecular functions and regulatory networks that might be dysregulated in patients. To do this, Kathi Zarnack worked closely with Dierk Niessing at the University of Ulm and the Helmholtz Center Munich.

To address these questions, the Computational RNA Biology group led by Kathi Zarnack analysed and integrated a series of large-scale experiments, which were conducted by Dierk Niessing's team. They used several high-throughput methods to understand which cellular RNAs are controlled by PURA and possibly misregulated in PURA patients. These included high-throughput RNA sequencing and mass spectrometry to determine the type and number of the messenger RNAs and proteins produced in PURA mutant cell as well as the so-called iCLIP technique to reveal which of the many messenger RNAs are bound by PURA. The main results were then confirmed using orthogonal biochemical methods and fluorescence microscopy. "Only with such an elaborate computational analysis are the data in their abundance at all interpretable and allow an understanding of the cellular tasks of the PURA protein," explains data analyst Melina Klostermann from the Zarnack group.

In the journal Nucleic Acids Research, the scientists now report that the PURA protein is predominantly found in the cytoplasm of cells, where it plays a role in important cellular mechanisms. These include the immune responses of cells, the function of mitochondria, and autophagy. In particular, the activity and networks of the so-called P-bodies, processing bodies that are central points of cellular mRNA quality control, appear to be strongly affected by reduced PURA levels. "Our hope is that by solving the molecular puzzle, our two labs have taken a first step toward future therapeutic approaches," Dierk Niessing said. However, there is still a long way to go before effective therapies are available, he added. Further studies must clarify which of these abnormalities are involved in causing the patients' severe symptoms.




In addition to the scientific investigation of PURA Syndrome, the two teams support patient families worldwide through lectures and counselling. They are also helping families in Germany to establish a national patient advocacy group. The work has been supported by the German Research Foundation, the Care-for-Rare Foundation, the PURA Syndrome Foundation and private donations, among others.


Contact:
Kathi Zarnack, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, kathi.zarnack(at)bmls.de, https://www.bmls.de/Computational_RNA_Biology/aboutus.html


Reference: Molitor, L.*, Klostermann, M.*, Bacher, S., Merl-Pham, J., Spranger, N., Burczyk, S., Ketteler, C., Rusha, E., Tews, D., Pertek, A., Proske, M., Busch, A., Reschke, S., Feederle, R., Hauck, S., Blum, H., Drukker, M., Fischer-Posovszky, P., K├Ânig, J., Zarnack, K.#, Niessing, D. # (2022). Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies. Nucleic Acids Research gkac1237. https://doi.org/10.1093/nar/gkac1237

 


 

 

 

 

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