Recently, a research team led by Professor Xu Wenqing from the School of Life Science and Technology (SLST) at ShanghaiTech, in collaboration with other researchers, published a significant study in the journal Proceedings of the National Academy of Sciences (PNAS). The paper, titled “De novo design of protein binders to stabilize monomeric TDP-43 and inhibit its pathological aggregation,” introduces an innovative research progress. For the first time, the team utilized AI-driven de novo protein design technology to develop a novel protein that can precisely bind and stabilize a key protein called TDP-43, effectively inhibiting its pathological aggregation. This achievement provides a new therapeutic strategy for neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease.
Many neurodegenerative diseases are characterized by the misfolding and pathological aggregation of specific proteins. In the case of ALS and frontotemporal lobar degeneration (FTLD), the abnormal aggregation of the TDP-43 protein is a crucial pathological feature. In the healthy state, a specific region of the TDP-43 protein, known as the amyloidogenic region, maintains a stable native helical conformation (a spiral shape). However, in the disease state, this region undergoes a structural change, leading to the formation of aggregations that are toxic to nerve cells.
For a long time, targeting this unstable protein region has been a major challenge, and effective therapies have been lacking. The ShanghaiTech team’s innovative approach directly addresses this issue. Using AI, they “designed from scratch” a protein binder specifically to attach to and stabilize the TDP-43 protein’s healthy helical shape. This effectively prevents it from twisting and starting the harmful aggregation process.
Design strategy of TDP-43 binding protein.
The research team rigorously validated the effectiveness of their designed protein binder. Experiments showed that the binder could attach to the TDP-43 protein with nanomolar binding affinity, which is an extremely strong and precise interaction.
Furthermore, the team demonstrated the binder’s efficacy by showing that it efficiently reduced TDP-43 pathological aggregation both in vitro (in test-tube experiments) and in cells. These results confirm that this new protein binder can successfully block the key step in the disease process.
The efficacy of designed binders in inhibiting the aggregation of TDP-43.
This study not only validates a promising new strategy for targeting ALS but also offers a template for addressing other neurodegenerative diseases. The same design principle could be applied to inhibit the aggregation of other pathological proteins, such as those implicated in Alzheimer’s and Parkinson’s diseases, paving the way for future treatments.
Sun Gangyu PhD ’25 from SLST and doctoral student Li Xiang from Shanghai Jiao Tong University are the co-first authors. Prof. Xu Wenqing and Research Associate Professor Wang Zhizhi are among the co-corresponding authors, with ShanghaiTech as the primary affiliation.