Alterations in the C9orf72 gene, located on human chromosome 9, promote RNA molecules that block key protein transport pathways, triggering molecular “traffic congestion” outside the nucleus of the brain, which can affect normal brain function, researchers said. In a recent study published in the international journal Nature, researchers from Johns Hopkins University have revealed how common gene mutations can trigger brain damage-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), according to Lin Wei of the Department of Neurosurgery at PLA Hospital 101. said that alterations in the C9orf72 gene, located on human chromosome 9, promote RNA molecules that block a key pathway for protein transport, triggering molecular “traffic congestion” outside the brain’s nucleus, which in turn affects normal brain function. According to researcher Jeffrey Rothstein, Ph.D., this common genetic mutation is associated with 40% of hereditary ALS cases, 25% of hereditary FTD cases directly, and approximately 10% of non-hereditary cases of both diseases. In FTD, for example, damage can cause problems with speech, understanding language, and emotional processing, while in ALS patients, degenerating neuronal cells can affect the function of the spinal cord as well as the brain, with patients eventually losing the ability to control their muscles. Rather than modifying the building blocks of DNA, the mutation, called C9orf72, triggers a six-nucleotide DNA strand to repeat hundreds or thousands of times, affecting cells that produce long strands of RNA repeats once the DNA is mutated; as early as 2013, researchers identified more than 400 specific proteins in cells where the repeating RNA strands could act directly; and in this paper study researchers focused on a protein called RanGAP, which mediates the effects of mutant RNAs in cells. In healthy cells, the protein RanGAP can transport molecules through the nuclear pore complex that connects the cytoplasm. In the article, using human brain cells derived from the ALS-associated C9orf72 mutation, the researchers found that the protein RanGAP is in an aggregated state outside the nucleus and that proteins that rely on RanGAP for transport into the nucleus do not flow through the nuclear pore . In another experiment, using Drosophila and human stem cells, researchers added antisense oligonucleotides to block the interaction of the antisense oligonucleotides with RanGAP and subsequently found that the disturbed nuclear pore complexes began to function again. The researchers do not know the exact mechanism of each stage of cell death in the brain and hope that more research will be done to clarify why C9orf72 mutations trigger ALS and FTD. Original source: Ke Zhang Christopher J. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport.