A Raw Nerve

At a walkathon one Saturday in September, nearly 5,000 people traced two miles of Chicago's lakefront to raise money for research into the progressive nerve disease that is thought to have killed baseball star Lou Gehrig. Janice Caliendo was there collecting blood samples from friends of those affected by the incurable disease to be used as controls in future genetic studies. Caliendo, a lab manager at Northwestern Memorial Hospital in the Streeterville neighborhood of the city, often attends these sorts of fundraisers, but this time she was getting more attention than usual.Her lab, headed by Northwestern University neurologist Teepu Siddique, has been all over the news recently for a study published in August in Naturereporting a new gene associated with the disease formally known as amyotrophic lateral sclerosis (ALS). “Breakthrough could lead to effective treatment for Lou Gehrig's disease,” read the LA Times's headline; “Cause of ALS is found, Northwestern team says,” wrote theChicago Tribune. In honor of the study, in fact, the event's organizers asked Siddique to lead the walkathon. Countless people approached Caliendo that day with the same questions: Does this mean there's a cure? Is there a blood test for ALS? Is there a drug to treat it?The answer to all these inquiries was 'no'. “It's not a cure, but people read into it what they want to hear,” Caliendo says. “I don't think they were disappointed, though, because it's still very good news. It's huge.”The study, some two decades in the making, was certainly newsworthy: it uncovered mutations in a gene called UBQLN2 that seemed to cause ALS in a handful of individuals with hereditary forms of the disease. But, according to Siddique, that's not even the exciting part. In the new paper, his team analyzed postmortem spinal cord tissue from dozens of people with different forms of the disease, including those who developed ALS spontaneously and didn't carry UBQLN2 mutations. To their surprise, Siddique and his colleagues found abnormal blobs of the ubiquilin-2 protein encoded by UBQLN2 in the neurons of every single individual they looked at.In Siddique's view, his study proves that all forms of ALS converge on a glitch in protein recycling that results in the accumulation of many types of proteins and the death of motor neurons. It's similar, he says, to the discovery decades ago that people with a genetic disease called familial hypercholesterolemia carry mutations in a receptor for 'bad' cholesterol. On the basis of those data, researchers designed drugs—statins—that are now taken not only by those affected by the rare disorder but also by the majority of people with all forms of heart disease in the developed world.“What we're showing here is a direct functional mechanism that causes disease,” Siddique says. “It's not just another cause; it's not just another pathology; it's a game changer.”However, many of Siddique's colleagues worry that his statements extend beyond what the data show. “To those of us who live in this world, it's great that there's another new gene,” says Jeffrey Rothstein, director of the Robert Packard Center for ALS Research at Johns Hopkins University in Baltimore. “But it's been way overblown.”Because of the media frenzy, the study ended up overshadowing two papers published exactly one month later that many ALS researchers find more significant but that didn't receive as much press coverage. The studies, published back to back on 29 September in Neuron, reported mutations in a region of chromosome 9 called C9ORF72 that crop up in as many as one-third of all familial cases of ALS. In contrast, mutations in all of the other ALS-associated genes combined—including UBQLN2—only account for about 25% of all familial cases.The Neuron studies, one of which included Rothstein as an author, bring the number of genes linked to familial forms of ALS up to 18, depending on how you count them. Yet most experts say the field is still far from understanding how any of these genes cause the disease—let alone how these genes relate to sporadic forms of ALS, which make up about 90% of all diagnoses. Plus, none of the genetic culprits are easy targets for drug development.“There is a lot of excitement about [these discoveries], and nobody is more excited than I am,” says Lewis Rowland, a neurologist at Columbia University Medical Center in New York. “But then there is this horrible fact that knowing the genetics of the disease doesn't help you treat the patients—either the genetic ones or the sporadic ones. ALS is just brutal as hell.”Read more at...Nature Medicine, November 2011.