The role of nucleocytoplasmic transport in C9orf72 amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons. This leads to progressive muscle wasting and paralysis, which ultimately leads to death of the patient on average 3 to 5 years after the first symptoms. In 10% of cases, ALS is a familial disease and the most important genetic cause are hexanucleotide repeat expansions (GGGGCC) in the C9ORF72 gene. In RNA, these expansions can give rise to non-ATG mediated translation resulting in five different dipeptide repeat proteins (DPRs). Through performing a RNAi-screen in a pure DPR fruit fly model (poly-PR and poly-GR), the host lab discovered that proteins involved in nucleocytoplasmic transport can influence DPR toxicity. In this PhD project, follow-up studies on this drosophila-screen will be performed. The effect of chemical inhibition of specific transport pathways on the DPR-induced degenerative eye phenotype in this fruit fly model will be investigated. We will also develop different nucleocytoplasmic transport models using cell lines as well as differentiated induced pluripotent cells (iPSCs) from patients with hexanucleotide repeat expansions in C9ORF72. As our working hypothesis is that the DPRs interfere with the import/export system of the nucleus, we will determine whether the presence of hexanucleotide repeats and/or DPRs interferes with the protein composition of the nucleus. We hope to get a better insight into the role of nucleocytoplasmic transport in ALS as the subcellular mislocalisation and cytoplasmic aggregation of different proteins (e.g. TDP-43 and FUS) is a hallmark of this fatal disease.

Jaar van publicatie:2021

Toegankelijkheid:Open