Happy 1st Birthday, C9orf72!Packard scientists are hard at work making new breakthroughs in the year following the discovery of the most common genetic cause of ALS. 
Packard investigator, Dr. Bryan Traynor, was part of an international team of researchers that identified the C9orf72 gene mutation one year ago.
One year ago, an international team of researchers, including Packard scientist Bryan Traynor, head of the Neuromuscular Diseases Research Unit at the National Institute on Aging, identified a mutation in the gene C9orf72 that is the most common genetic cause of ALS and frontotemporal dementia (FTD). This mutation is the cause of 40% of familial ALS in European populations, and up to 7% of sporadic ALS in Caucasians.
“The ALS and FTD communities were very excited about this discovery, not just because of its high frequency, but also because it opened up a new disease mechanism that we could go after,” Traynor said. In the year following the announcement of the link between C9orf72, ALS, and FTD, 117 additional studies have been published, at the rate of more than two studies per week. The original paper has already been cited over 130 times by other scientists. This past March, a special issue of the journal Brain was devoted to papers about C9orf72. At a recent conference on FTD in Manchester, England, nearly all of the researchers mentioned the mutation in their talks. Preliminary studies have indicated that C9orf72 is one of the most common genetic causes of neurodegenerative disease. "This has been a very exciting year for the ALS and FTD research communities. C9orf72 is significant not only because it is the most common gene identified to date to cause familial ALS, but also because it is found in a large percentage of what were thought to be sporadic cases. This is a key element of the vast majority of ALS patients," said Piera Pasinelli, Science Director at the Packard Center. "The change to research began immediately, and within a few days after mutations in C9orf72 were reported, Packard was building a team of researchers to work on this new gene with multiple approaches. A year has passed and lots of work has been done, although we haven't seen the results of it yet because it takes time to go from the original discovery to building tools to all of the necessary follow-up studies. And for C9orf72 it may require a bit more as understanding this gene will be difficult due to the complex nature of this defect. It is promising, however, that the defect in C9orf72 looks a lot like a mutation in another disease known as myotonic dystrophy. We might be able to learn from that field mainly to learn how to best use gene inactivation techniques to develop therapies." Even as he published his discovery of C9orf72, Traynor knew that one of his first priorities was determining how the mutation could lead to ALS. The type of mutation in C9orf72 is a repeat expansion, which means six letters of the DNA code are repeated, or expanded, hundreds or thousands of times within the gene. Repeat expansions can cause disease by one of the following ways: the repeat expansion can disrupt the gene's normal function, or the repeat expansion itself can be toxic to the cell. Scientists had no idea which of these options was the result of C9orf72. Nor, Traynor added, are these options mutually exclusive: the loss of the normal function of the C9orf72 gene combined with the toxic RNA could lead to ALS. To try and follow the path from repeat expansion to disease, Packard scientists have begun creating animal models. Packard scientist Phil Wong, a neuroscientist at Johns Hopkins University, is one of those scientists. He says that his ongoing studies of C9orf72 may also provide insights on how other mutations in genes like TDP43 and FUS lead to ALS. One thing that all of these mutations have in common is that they lead to protein aggregates, clumps of proteins that can accumulate in the nucleus and cytoplasm of the cell. Cells taken from C9orf72 ALS patients who don't have mutations in the TDP-43 gene have TDP-43 protein aggregates, which could mean that disruptions in TDP-43 function are the final step in a common pathway to ALS, Wong says. Since early experimental results indicate that C9orf72 may be affecting RNA metabolism, like TDP-43 and FUS, studying this repeat expansion could lead to discoveries that apply to a larger proportion of ALS patients than just those with the C9orf72 expansion. “This discovery is a paradigm shift in terms of the number of patients who are affected by this mutation, both with ALS and with FTD, confirming the idea that these two diseases share a common genetic and pathological spectrum,” Wong said. Jiou Wang, also a Packard neuroscientist at Johns Hopkins, has been developing animal models both in the worm Caenorhabditis elegans and in mammals. Although worms might not seem very similar to humans, the simpler system of C. elegans has allowed Wang to learn a lot about the links between mutations in TDP-43 and ALS. He hopes that the use of C. elegans, when combined with insights from mammalian models, will help elucidate the links between the C9orf72 repeat expansions and ALS, as well as identifying potential therapeutic targets. “We know little about the nature of the hexanucleotide repeat expansion and hardly anything about the function of the C9orf72 protein. But now we have molecular handles for new investigations towards understanding a common form of ALS,” Wang said. Nonprofit organizations like Packard and ALSA (the ALS Association) have played a key role in the development of these animal models by targeting funding to specific efforts that will help create the best models in the shortest amount of time, Traynor said. This will help speed up the process and prevent a duplication of effort. Although researchers have made tremendous progress in the last year at developing animal models for C9orf72, it takes time to build the model, test it experimentally, and write it up for publication. The researchers caution that it will take time before these animal models can be used by other scientists in the ALS field. When these models are ready, however, the research community will be poised to make good use of them. Good animal models will help accelerate the movement of potential therapeutic targets to treatment trials. Since the C9orf72 mutation is so common, scientists will have the chance to develop trials targeted specifically at individuals with this repeat expansion. These trials, in turn, will inform other areas of ALS research. “It’s very gratifying to see that all of these things are working out, and to see the research moving back towards the patients, so that they can benefit from the knowledge that we’ve gained,” Traynor concluded. –– Carrie Arnold
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