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Nuclear Transport Problems Linked to ALS and FTD


DNA is made up of building blocks called nucleotides. In the mutated C9orf72 gene, a sequence of six nucleotides is repeated many times more than are typical. These repetitive stretches of DNA produce RNA molecules that can interfere with proteins in the cell. The RNA also generates toxic proteins called dipeptide repeat proteins. However, until now, it was unknown what specific cellular systems were impaired by these two products of the mutation.


Both amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are caused by the death of specific neurons. In ALS, this leads to movement difficulties and eventually paralysis, while in FTD, patients experience problems with language and decision making. Past research has connected a specific mutation in the C9orf72 gene to 40% of inherited ALS cases and 25% of inherited FTD cases, as well as nearly 10% of non-inherited cases of each disorder. Recent experiments, conducted in yeast, fruit flies, and neurons from patients, found that the mutation prevents proteins and RNA from moving between the nucleus and the cytoplasm that surrounds it.


According to an article published in Nature (25 August 2015), 3 teams of scientists supported by the National Institutes of Health showed that a genetic mutation in the C9orf72 gene may destroy neurons by disrupting the movement of materials in and out of the cell’s nucleus. The results, provide a possible strategy for treating the two diseases. Evidence that the mutation impairs nuclear transport in neurons was derived from skin cells grown from patients. One team showed that these neurons have much more RNA in the nucleus compared to those created from healthy control cells, implying that the mutation prevents RNA from leaving the nucleus. The other two groups discovered that the patient-derived neurons had trouble bringing certain proteins into the nucleus as well. One group of investigators focused on how the abnormal RNA produced by the C9orf72 mutation affects a protein called RanGAP, which is essential for transporting materials into the nucleus. Building on previous work, the group confirmed that the RNA strands bind to RanGAP in brain tissue from patients with the mutation and stop the protein from performing its function. The team then treated those cells with compounds that prevented this interference and found that this eliminated the transport defect, allowing proteins to get inside the nucleus. Similarly, increasing production of RanGAP in fruit flies reduced neuronal deterioration and motor problems caused by the mutation.


In addition to the work with the lab-grown neurons, one team explored the mutation’s effects by inserting eight, 28, or 58 copies of the repetitive DNA sequence into fruit fly neurons. By doing this it was found that additional copies caused more harm to the cells. The group then performed a genetic “screen“ in which they systematically mutated other fly genes to find ones that increased or decreased this damage. Many of the genes they found code for nuclear transport proteins, which regulate the movement of molecules in and out of the nucleus. The authors noted that they were amazed to find 18 genes that relate to nucleocytoplasmic trafficking, and that this indicated that they were on to something very important.


Taken together, the three studies suggest that therapies designed to increase nucleocytoplasmic transport may be effective for treating some forms of ALS and FTD.



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