Unravelling the protective effect of RNA-binding proteins on the RNA toxicity in amyotrophic lateral sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a dramatic neurodegenerative disorder characterized by the selective death of the motor neurons in the brain and the spinal cord and leads to the death of the patient on average 2 to 5 years after the detection of the first symptoms. In 1 out of 10 patients, ALS is a familial disease and in the majority of these cases a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene is responsible for the disease (C9-ALS patients). We have established a transient zebrafish model for this form of ALS and published data strongly indicating that RNA toxicity (induced by the hexanucleotide repeat  containing RNA) plays an important role in this ALS model. Preliminary data also indicate that we can counteract this RNA toxicity by co-expression of different RNA-binding proteins. The aim of this proposal is to further characterize this protective effect and to investigate the underlying molecular mechanism using both a transient and a stable zebrafish model. In addition, we will use motor neurons obtained from induced pluripotent stem cells (iPSCs) derived from C9-ALS patients. In a second part, we will check whether the presence of the repeats has an effect on the expression of the RNA-binding proteins using the different models as well as post-mortem material of C9-ALS patients. Overall, we will get a better insight into the role of RNA-binding proteins in ALS, which could lead to new therapeutic targets.