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New Genes, New Clues About ALS

January 18, 2011

New gene discoveries have quickened the pace of research on the causes of ALS.  Those discoveries were the focus of several presentations and many conversations among scientists at the ALS/MND Symposium in Orlando, sponsored by the Motor Neurone Disease Association, and hosted by The ALS Association.

The discovery of VCP, the newest gene known to cause ALS, was announced just prior to the meeting.

Two other genes, TDP-43 and FUS, were discovered within the past two years and have become the subject of intense research.  They join SOD1, the first gene discovered for ALS and still the most common genetic cause known.

Virginia Lee, Ph.D., of the University of Pennsylvania, was a co-discoverer of TDP-43.  “This discovery has had an enormous impact” on the understanding of neurodegenerative diseases, for two reasons, she said.  First, TDP-43 mutations can also cause another neurodegenerative disease, called frontotemporal dementia, suggesting the two diseases are two ends of a single spectrum.  Second, the involvement of TDP-43 points to RNA processing as a potentially central mechanism in disease.  Cells use RNA for a variety of processes, most importantly for relaying genetic messages from the nucleus, where they are stored, to the cytoplasm, where they can be used to create protein.

Both TDP-43 and FUS are RNA-binding proteins, meaning they interact with RNA to help it do its job.  It is not yet clear how mutations in these two proteins cause disease, but researchers are looking closely at the protein-RNA interactions, to see whether the mutations that cause disease disrupt the normal activity of RNA as a result.  “The more we understand these pathways, the better we can use than information to identify new targets for treating ALS.  This is a really exciting time for learning more about the causes of ALS, and trying to find disease-modifying therapies,” Dr. Lee said.

Tom Maniatis, Ph.D., of Harvard University, is examining the effect of TDP-43 and FUS mutations on gene expression in motor neurons.  The goal is to find “the needle in the haystack,” the change in expression that leads to disease, rather than the many others that are a result of it.  For reasons that are not yet clear, TDP-43 mutations appear to cause changes in expression that are opposite to those of FUS mutations, despite the fact that both cause ALS.  Further research may uncover the link between the two that sheds light on a common pathway.  Other researchers noted that the two proteins interact, and that interaction may increase when one or both are mutated.

The effects of mutations in these genes are being explored in a variety of models, each chosen to highlight one or more aspects of the disease process.  The hope is that this multi-pronged approach has the best chance of revealing the true problem each mutation causes.

Another recently discovered gene, called optineurin, is only found in a handful of families, but researchers are hoping it may reveal disease mechanisms common to many forms of ALS.  Mutations in optineurin are known to increase inflammation, a process that may damage motor neurons, through another molecule called TNF-alpha.  “If this hypothesis is true,” said Ryuji Kaji, M.D., of Tokushima University in Japan, “inhibition of TNF-alpha may be a key to disease-modifying therapy.”  He pointed out that there are many drugs already known to inhibit this molecule, suggesting it may be possible to quickly test this possibility.

“There are still more ALS genes to be discovered,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D. She noted that the most recently discovered gene, VCP, which occurs on chromosome 9, is not the only ALS-causing gene there.  Further work will be needed to discover this still-unknown gene and to identify others that cause the disease.  “By finding these genes, and understanding the pathways each works in, we can piece together a picture of ALS that will lead us to new treatments.  Each gene we discover brings us closer to that goal.”

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