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Researchers at Goethe University, Johannes Gutenberg University Mainz and Kiel University discover possible method for preventing protein aggregates – Cluster4Future PROXIDRUGS research project
2500 new cases of amyotrophic lateral sclerosis are diagnosed every year, making it a relatively rare but very serious disease of the nervous system. A cure is not yet possible. ALS slowly destroys the motor neurons in the brain and spinal cord responsible for voluntary muscle control. The result is progressive muscle paralysis, leaving many patients wheelchair dependent. As the disease progresses, individuals find it increasingly difficult to speak, swallow, and breathe.
In ALS, poorly soluble protein aggregates accumulate in motor neurons. Among other proteins, these aggregates consist of TDP-43, which plays various critical roles in cellular RNA metabolism. While in healthy cells TDP-43 is mainly found in soluble form in the cell nucleus, in ALS patients it forms poorly soluble aggregates that mainly accumulate outside the cell nucleus. This means that TDP-43 loses its functionality, as well as ultimately leading to the death of the motor neurons.
As part of the Cluster4Future PROXIDRUGS funded by the Federal Ministry of Education and Research (Germany), researchers from the universities of Frankfurt, Mainz and Kiel have now discovered a way to prevent the formation of harmful TDP-43 aggregates in cultured cells. To do this, scientists led by Kristina Wagner, Dr. Jan Keiten-Schmitz and Professor Stefan Müller from the Institute of Biochemistry II at Goethe University exposed cells to stress, for example by increasing the temperature or using a chemical substance. As a result, some TDP-43 was released from the cell nucleus into the cytosol, where it accumulated in so-called stress granules.
“The formation of such stress granules is a normal process and serves the cell as a temporary protective space for proteins so that they are immediately available to the cell once the stress has subsided,” explains Keiten-Schmitz. “However, if TDP-43 is mutated, as it is in the cells of many ALS patients, the stress granules persist, increasingly solidify and ultimately damage the neurons.”
The scientists successfully prevented TDP-43 from leaving the cell nucleus under stress by linking it with the cell's “roadside assistance” – a protein called SUMO – which directed TDP-43 to a cellular “mechanic”, the so-called nuclear bodies. “As a result, TDP-43 remains soluble, and the nuclear bodies - like a mechanic - ensure that harmful forms of TDP-43 are restored or broken down by the cellular recycling system,” says Kristina Wagner, a first author of the study. Insoluble protein aggregates that damage or even kill cells would therefore be prevented from forming in the first place.
The team of researchers is now looking for future drug candidates in the form of chemical compounds that bring SUMO and TDP-43 together. PROXIDRUGS principal Investigator Müller explains: “Our cell culture experiments provide a first proof-of-principle: this pathway can help cells to limit disease-promoting TDP-43 aggregates. Even if the road to developing a possible drug for treating ALS is still very long, it is definitely worth pursuing this approach further. After all, TDP-43 aggregates are also found in other neurodegenerative diseases, such as frontotemporal dementia (FTD) and in around half of all Alzheimer's patients.”
Background information:
https://www.als.org, https://www.targetals.org, https://lesturnerals.org, https://www.alshf.org/what-is-als
Goethe-Universität Frankfurt
Institut für Biochemie II
Prof. Dr. Stefan Müller
Gruppenleiter SUMO Signaling
+49 (0)69 6301-83647
ste.mueller@em.uni-frankfurt.de
https://biochem2.com/people/mueller-stefan
Dr. Jan Keiten-Schmitz
Tel. +49 (0)69 6301-6698
keiten-schmitz@em.uni-frankfurt.de
https://biochem2.com/people/keiten-schmitz-jan
Bluesky: @goetheuni.bsky.social @ibc2-gu.bsky.social
Linkedin: @Goethe-Universität Frankfurt
Kristina Wagner, Jan Keiten-Schmitz, Bikash Adhikari, Upayan Patra, Koraljka Husnjak, François McNicoll, Dorothee Dormann, Michaela Müller-McNicoll, Georg Tascher, Elmar Wolf and Stefan Müller: Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks. Nature Chemical Biology (2025),
10.1038/s41589-025-01886-4
https://www.nature.com/articles/s41589-025-01886-4
The microscopy images show the nuclei of cultured human cells. On the left, the protein TDP 43 (gree ...
Dr. Jan Keiten-Schmitz
Goethe-Universität Frankfurt
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The microscopy images show the nuclei of cultured human cells. On the left, the protein TDP 43 (gree ...
Dr. Jan Keiten-Schmitz
Goethe-Universität Frankfurt
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