Detecting harmful protein aggregation to develop new therapeutics for neurodegeneration

Target-43: Therapeutic Targeting of TDP-43 Aggregation Intermediates through Mass Spectrometry Innovations

Many neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia, and some forms of Alzheimer’s disease, are associated with harmful aggregation of a protein called TAR DNA-binding protein 43 (TDP-43). These protein clumps form gradually in brain cells and interfere with normal cellular processes, eventually leading to the loss of nerve cells. Increasing evidence shows that the earliest aggregation intermediates, known as oligomers, may be the most toxic. However, these early structures are extremely difficult to detect because they are small, short-lived, and highly variable.

This project aims to develop new analytical tools that can detect these early oligomers. The research team will use a powerful technique called ion mobility mass spectrometry, which can separate different oligomers based on their size, shape, and charge. This allows to distinguish between single protein molecules and harmful, early oligomers that form during disease progression. By understanding exactly how these harmful structures appear and grow, we can better identify where therapeutic interventions is most effective.

The project will test new therapeutic antibodies developed by the Dutch biotechnology company VectorY Therapeutics. These antibodies are designed to bind specifically to harmful protein forms and prevent them from forming larger aggregates. By combining advanced analytical measurements with cellular experiments, the project will determine how antibodies interact with different toxic protein structures to guide future drug development.

The research will be carried out through a close collaboration between Vrije Universiteit Amsterdam and VectorY Therapeutics. This partnership combines academic expertise in advanced mass spectrometry with industrial expertise in developing therapies for neurodegeneration.

Ultimately, this project aims to accelerate the development of new treatments for neurodegenerative diseases and create a technology platform that can support future drug discovery.

Summary

Neurodegenerative diseases such as Alzheimer’s disease or ALS are hallmarked by the toxic protein aggregation of TDP-43 in the brain. TARGET-43 develops advanced mass spectrometry methods to identify early toxic protein oligomeric structures and study how therapeutic antibodies prevent their formation, helping researchers design more effective treatments.

Technology Readiness Level (TRL)

3 - 6

Time period

48 months

Partners