Nature Medicine | Spoonful of Medicine

NEWS FEATURE: A raw nerve

By Virginia Hughes

nm1111-1333-I1.jpgAt 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 Nature reporting 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 the Chicago 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.”

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