Rational targeting of FUS and TDP-43 protein assemblies for diagnostics and treatment of ALS

A protein is said to have prion-like behaviour when it fulfills two major criteria: first, it must be able to cause other normally-folded proteins to change their shape and adopt a toxic shape. Second, it must trigger a chain reaction, moving from cell to cell creating a domino effect of toxic protein misfolding and aggregation that spreads throughout the nervous system. Well-known prion diseases include scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in humans.

Some researchers believe that a prion-like mechanism may contribute to disease progression in ALS and that the size and shape of the aggregates differ depending on the protein involved or even the specific mutation within a particular protein. The difference in the aggregates formed could help to explain the varying symptoms observed in people living with ALS.

With this grant, Dr. Stepanova will use computational methods to predict the structure of abnormal protein aggregates formed by two ALS-linked proteins, TDP-43 and FUS. Results from the sophisticated computational analyses will provide researchers with the framework to design antibodies that can target these aggregates and hopefully slow or stop the toxic domino effect.

Antibodies are proteins naturally produced by the immune system to protect the body against foreign invaders like bacteria and viruses. Antibodies, however, are also commonly used as a tool in research because they can be designed to bind to specific proteins within the body making them ideal candidates for detecting biomarkers or even as treatments for various diseases.

In collaboration with Dr. Wille, the team will create antibodies capable of specifically binding to the toxic protein assemblies identified in the initial computational studies. To validate whether these are relevant in a human context, the antibodies will be tested in brain tissue samples donated from ALS patients. If the antibodies successfully bind, this will suggest that the predicted protein aggregate structures are involved in ALS diseases processes and reveal new targets for future drug development. Additionally, the already developed antibodies could be examined further to assess their potential as tools to detect diagnostic biomarkers or even as treatment options for ALS.