19 Apr 2025 - Cellular ‘Roadside Assistance’ may prevent harmful TDP-43 aggregates
The fluorescence microscopy images show the nuclei of cultured human cells. On the left, the protein TDP‑43 (green) is seen distributed within the cell nucleus along with nuclear bodies (red), which act as repair sites. When TDP‑43 is damaged by stress or mutations and coupled with SUMO proteins (right image), it is transported to the nucleoli (arrows), where it is protected from aggregation.
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 research team led by IBC2 researchers Kristina Wagner, Jan Keiten-Schmitz, and IBC2 Vice Director Stefan Müller at Goethe University Frankfurt, in collaboration with Johannes Gutenberg University Mainz and Christian-Albrechts University Kiel, succeeded in interrupting this process in cultured cells.
The team demonstrated that 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 the repair system by linking TDP-43 with the protein SUMO—the cellular roadside assistance—which redirected TDP-43 to PML nuclear bodies, the cellular mechanics, where it remains soluble and is either repaired or degraded by the cell's own recycling system. This mechanism helps prevent the formation of insoluble aggregates at an early stage.
The IBC2 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.”