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Breakthrough in neuroresearch: TDP-43 as the key to fighting ALS!
Researchers at Goethe University Frankfurt are developing new approaches to combat TDP-43 clumps that promote ALS and Alzheimer's.
Breakthrough in neuroresearch: TDP-43 as the key to fighting ALS!
Neuroscientists at Goethe University have made remarkable progress in the fight against amyotrophic lateral sclerosis (ALS). A recent study shows that the defective protein TDP-43, which is linked to neurodegenerative diseases such as ALS and Alzheimer's dementia, can be successfully protected from harmful clumps. This study was carried out as part of the PROXIDRUGS future cluster, which focuses on the development of a new class of active ingredients. Every year, around 2,500 people in Germany are diagnosed with ALS, a potentially fatal disease that attacks motor nerve cells in the brain and spinal cord and leads to progressive muscle paralysis.
TDP-43 is an essential protein active in cellular RNA metabolism and plays a central role in regulating splicing, mRNA stability and miRNA biogenesis. In ALS patients, TDP-43 tends to form poorly soluble aggregates that accumulate outside the cell nucleus and contribute to the death of motor nerve cells. This abnormality is not only limited to ALS, but is also found in other neurodegenerative diseases such as frontotemporal dementia and Alzheimer's disease, highlighting the central role of TDP-43 in neurodegeneration. In fact, almost every second Alzheimer's patient suffers from TDP-43 pathology, especially in advanced stages of the disease.
mechanisms at work
In their experiments, the researchers placed cells under targeted stress, such as increased temperature. This caused the TDP-43 protein to migrate from the nucleus into stress granules, which act as temporary shelters for important proteins. To prevent TDP-43 from exiting the cell nucleus, the research team coupled the protein with SUMO, a small ubiquitin-like modifier. This coupling directs TDP-43 to nucleoli that are specifically capable of repairing or degrading harmful forms of proteins.
The publication of the study entitled “Induced proximity to PML protects TDP-43 from aggregation via SUMO–ubiquitin networks” appeared in the renowned journal Nature Chemical Biology in 2025. The results suggest that therapeutic approaches that promote the coupling of TDP-43 to SUMO should be considered as a promising avenue for the development of new drugs in the treatment of ALS and related diseases.
A look into the future
Research on TDP-43 is gaining momentum as new insights into its role in various neurodegenerative diseases come to light. In addition to the diseases already mentioned, the involvement of TDP-43 in Huntington's disease and Niemann-Pick C disease is also being investigated. TDP-43 conductors therefore have the potential to attract great attention as therapeutic targets in neurology.
In summary, the Goethe University study shows that innovative approaches to dealing with TDP-43 pathology can emerge and that this offers new hope for patients with ALS and other neurodegenerative diseases. These developments could hold the key to effective therapies that change the fate of many affected people.