3-D Changes in DNA May Lead to a Genetic Form of Lou Gehrig's Disease

A new discovery by Jiou Wang, Ph.D., and his colleagues at Johns Hopkins University that a mutation in the C9orf72 gene can cause neurodegeneration, or altering the shape of DNA which, in turn, kills the DNA molecule. Mutations in this C9orf72 gene causes amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), as well as frontotemporal degeneration (FTD). They also believe this mutation might be associated with Alzheimer's and Huntington's disease. In a normal C9orf72 gene, the nucleotide sequence repeats between 2-25 times, however, the mutation causes the gene to repeat tens of thousands of times. With these extra repetitions, the shape of the DNA molecules changes from the twisted ladder to G-quadruplexes (image below), which are stacks of square-shaped molecules called G-quartets. This mutation has serious effects on how the genetic message is processed. The mutated DNA forms a DNA-RNA hybrid structure called R-loops. The R-loops and G-quadruplexes disrupt the transcription process, thus patients with this mutation produce short transcripts. The cell functions abnormally because of these short transcripts. Dr. Wang also determined that this mutation effects the nucleolus which contains the cell's DNA and is the site for initial protein assembly. Dr. Wang teamed up with Jeffery D. Rothstein, M.D., also from Johns Hopkins University to observe the effects of the C9orf72 mutation on nucleolin which is a key protein inside the nucleolus. Their research show that the short transcripts bound to the nucleolin has toxic effects on the cell. In a healthy cell, the nucleolin is only present in a certain area of the nucleus, while in the cells from the ALS patients, nucleolin is present throughout the nucleus. They hypothesize that abnormal distribution of nucleolin kills the cell and results in ALS and FTD.

(The above image shows a G-quadruplex configuration)
I find this new discovery very important because now we know what happens on the molecular scale for ALS and FTD to occur. Scientist can now do experiments on how to stop this phenomenon from happening. This discovery also puts the foot in the door for a cure for Alzheimer's and Huntington's disease. This could be the start for some incredible discoveries in the future regarding ALS, FTD, Alzheimer's and Huntington's disease.