FTD/ALS are complex neurodegenerative disorders with a considerable clinical and pathological overlap. The G4C2 repeat can be translated into toxic dipeptide repeat proteins (DPRs) by non-ATG initiated (RAN) translation. These DPRs are toxic and found throughout the brain of affected C9ALS/FTD patients.
We investigate the protein-toxicity of DPRs in vivo using zebrafish and mice as models. In fertilized eggs of the zebrafish we can inject the DPRs to evaluate their relative toxicity and their impact on normal cell function. In mice we study the formation of all DPRs over time. We try to find modifying factors that provide information about the formation and spreading of the DPRs.
Valuable insights into the cellular toxicity of DPRs and the underlying molecular mechanisms will be obtained through this project. Ultimately, knowledge about the pathogenesis of FTD/ALS will enhance and may identify potential targets for therapeutic intervention.