Researchers have discovered how the most common genetic cause of two devastating brain disorders disrupts the normal function of nerve cells. The finding suggests a possible new treatment strategy for amyotrophic lateral sclerosis (ALS), which is also called Lou Gehrig’s disease, and frontotemporal dementia (FTD).
The mutation occurs in a gene named C9ORF72.
Scientists at St. Jude and the University of Massachusetts Medical School found the mutation blocks movement of RNA and other molecules in and out of the cell’s command center or nucleus. That disrupts important cell processes, such as assembling the proteins that do the work of cells.
Investigators checked nerve cells generated from people with the mutation and found that RNA built up in the cell nucleus. That did not happen in nerve cells from people without the mutation. RNA also did not build up in the nucleus of non-nerve cells from patients with the mutation.
ALS and FTD involve the deterioration and death of nerve cells in the brain and spinal cord. That leads to muscle weakness, paralysis plus other symptoms as well as problems walking or swallowing. There are no treatments to halt or reverse the process. Most patients die within five years of diagnosis.
“This study reveals the key defect that that we need to reverse in treatment, possibly by knocking out or silencing the mutant gene,” said J. Paul Taylor, MD, PhD, Cell and Molecular Biology chair and a Howard Hughes Medical Institute investigator.
Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525(7567:129-33, 2015. doi: 10.1038/nature14974.