Investigators reported evidence the mutation in C9ORF72 gene implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) interferes with the movement of RNAs and proteins into and out of the nucleus.
Instructions for assembling new proteins are encoded in DNA in the cell nucleus. RNA carries this information out of the nucleus to the cytoplasm where proteins are made. The discovery reveals that the most common gene mutation in ALS and FTD blocks this transfer of information, setting the stage for the deterioration and death of neurons in the brain and spinal cord.
By sequentially knocking out one copy of each gene, researchers identified 18 modifier genes whose loss led to an easing or worsening of symptoms. The 18 genes were all involved in the nuclear transportation system.
Some genes encoded proteins that were part of the nuclear pore complex; others were part of the machinery that coordinates the export of RNA from the nucleus and the import of proteins needed for the nucleus to function properly.
When researchers compared RNA concentration inside and outside the nucleus, they found RNA density was about 35 percent greater in neurons from patients with the mutation than in those without. The study included neurons generated from five patients with C9ORF72 mutations and three without.
The mutation did not have a similar impact on RNA concentrations in skin fibroblast cells from the same patients. That suggests the damage caused by C9ORF72 mutation is limited to brain cells.