Cellular ‘Roadside Assistance’ may prevent harmful TDP-43 aggregates
- Jacqueline Kandsberger
- 5 days ago
- 2 min read
Updated: 14 minutes ago
In their publication in Nature Chemical Biology PROXIDRUGS researchers and collaborating universities have discovered a way to prevent harmful TDP-43 aggregates in cells under stress by redirecting the protein to the cell’s own repair system—offering promising new strategies for treating ALS and other neurodegenerative diseases.
The formation of insoluble protein aggregates in nerve cells is a key feature of Amyotrophic Lateral Sclerosis (ALS) and other neurodegenerative diseases such as Alzheimer’s and Frontotemporal Dementia. A particularly important protein in this process is TDP-43, which tends to form aggregates under stressful conditions.
As part of the Cluster4Future PROXIDRUGS initiative, funded by the German Federal Ministry of Education and Research (BMBF), a research team led by Kristina Wagner, Jan Keiten-Schmitz, and Principal Investigator Stefan Müller from Goethe University Frankfurt, in collaboration with Johannes Gutenberg University Mainz and Christian-Albrechts University Kiel, succeeded in interrupting this process in cultured cells.
Under stress, TDP-43 exits the cell nucleus and accumulates in so-called stress granules—temporary protective spaces for proteins. Mutated TDP-43, as found in many ALS patients, does not resolve but instead solidifies into harmful aggregates. In their experiments, the research team redirected TDP-43 to a cellular repair hub by linking TDP-43 with the protein SUMO—a cellular roadside assistance. This redirected TDP-43 to PML nuclear bodies, where it remains soluble or is degraded by the cell's own recycling system. This mechanism helps prevent the formation of insoluble aggregates at an early stage.
The PROXIDRUGS researchers are currently seeking small molecules that can link SUMO and TDP-43—some promising candidates have already been identified. “Our cell culture experiments provide a first proof-of-principle: this pathway can help cells to limit disease-promoting TDP-43 aggregates,” explains Müller. “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.”
