TDP43 Protein Neurodegeneration: The Mechanism


Understanding the underlying causes of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS), and establishing effective treatments, is a major challenge. TDP43, a highly unstable protein, has been associated with the emergence and progression of these disorders in recent studies conducted by researchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL). The importance of TDP43 in neurodegeneration and future directions for new therapies are discussed in this article.

TDP43 Protein Neurodegeneration: Uncovering the pathogenic effects

Scientists at EPFL, in collaboration with researchers at the University of Pennsylvania, have discovered that TDP43 aggregates are not pathogenic until broken down by enzymes. These exposed surfaces attract normal TDP-43 proteins, leading to the formation of more aggregates and contributing to neurodegeneration.

Implications for therapeutic strategies:

The results of this study offer promising prospects for the development of therapeutic interventions to combat TDP43 neurodegeneration. Inhibition of enzymes can slow TDP43 aggregate formation. Identifying these enzymes and studying their inhibition could pave the way for new treatments targeting TDP43 aggregation, ultimately slowing disease progression in conditions such as ALS.

Early diagnosis and follow-up are essential::

The results of the study also have important implications for the early detection and monitoring of neurodegenerative diseases, including ALS. TDP-43 fibers are difficult to detect due to their spherical coating. Identifying the cleavage mechanism highlights why imaging agents and diagnostic tools that focus on intact TDP-43 fibers face challenges. The development of new imaging agents and techniques capable of accurately detecting TDP43 aggregates will enable early diagnosis, monitoring of disease progression, and evaluation of the efficacy of emerging therapies.

Importance of studying complete proteins:

TDP-43 is a highly unstable protein that assembles rapidly into a variety of structures, posing challenges for scientists attempting to reproduce pathological-type aggregates. EPFL’s research emphasizes the importance of studying the complete proteome to develop effective drugs.

Implications and future research:

The ability to produce TDP-43 fibers with base sequences similar to those found in patients’ brains opens the door to further investigations. Determining whether unmasked fibrous pulp shares the same structure could establish a state-of-the-art system for reproducing real pathology in vitro. This advance holds enormous potential for understanding how disease-related mutations and protein modifications affect TDP-43 accumulation. It may also facilitate the Development of new drugs to prevent TDP-43 accumulation, neutralize pathogenicity, and detect aggregates.


The EPFL scientists’ study revealed a role for the highly unstable TDP43 protein in neurodegenerative diseases. By identifying the mechanism that leads to TDP-43 aggregation and understanding its pathogenic effects, researchers can explore potential therapeutic strategies and advance early diagnosis methods. The importance of a complete and repeated proteomic study.

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