The mechanism of mutant C9orf72 in the pathogenesis of Amyotrophic Lateral Sclerosis/Frontotemporal Lobe Degeneration.

Amyotrophic Lateral Sclerosis (ALS) is a devastating degenerative disease of motor nerves in brain and spinal cord. It results in muscle weakness and atrophy, and is relentlessly progressive. It often is fatal only three years after onset. ALS forms a continuum with another disease, characterized by behavioral changes, called frontotemporal lobe degeneration (FTLD). ALS-FTLD is  hereditary in about 10 % of patients. In about half of these, the disease is caused by a change in the gene called C9orf72. Its function is unknown. The change consists of the abnormal expansion of a stretch of genetic material (DNA), that contains repetitive sequences, called repeats. It is unknown how this repeat expansion in C9orf72 induces neurodegeneration. In the present project we intend to study this by generating animal and cellular models for C9orf72(G4C2)exp –associated ALS/FTLD. In addition, we will screen these models in order to identify factors that enhance the toxicity of C9orf72(G4C2)exp or, even better, neutralize this toxicity. These factors may indeed by targets for therapeutic intervention strategies. The models that we plan to generate will be yeast, fly and zebrafish. These have been demonstrated in previous research by us and others, to be very suited to study the mechanism of disease induced by expanded repeats. Furthermore, using stem cell technology, we will establish cultures of nerve cells from patients with C9orf72(G4C2)exp-associated ALS/FTLD, to investigate whether what we have found in yeast, fly and fish, can be confirmed in a “human model” for this disease.