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C9orf72 dna streng
Research project  |  R. Willemsen

Amyotrophic lateral sclerosis (ALS) and frontaltemporal dementia (FTD)

Status: Ongoing

Both ALS and FTD can result from a GGGGCC repeat expansion in the C9orf72 gene. While normally the repeat is present 2-8X, in ALS/FTD patients it can be expanded 100x to 4000x.

What we do

About our project

Background information 

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.

Overall aim

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.

Research method 

RNAs that code for DPRs are injected in fertilized zebrafish oocytes. The amount of death cells in the brain will be quantified using a Sec-A5 reporter line in which apoptotic cells become fluorescently labeled.

amyotrophic lateral

In addition, we have generated an inducible transgenic mouse expressing G4C2 repeat of 36 units. These mice also express DPRs and allow studying the pathogenesis of FTD/ALS.

Desirable outcome

We expect to obtain valuable insights into the cellular toxicity of DPRs and the underlying molecular mechanisms. Ultimately, we will learn more about the pathogenesis of FTD/ALS and may identify potential targets for therapeutic intervention.



Our team