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Gubitz is also pushing ALS researchers to collaborate more closely and to identify the strengths and weaknesses of each animal model. To that end, at the Society for Neuroscience meeting in November, Gubitz and Lucie Bruijn, of the ALS Association, gathered 125 scientists working with ALS animal models for an idea exchange. "We're trying to figure out which models should be made more broadly available," she says.
New methods to study ALS are sorely needed, as the disease remains a frustrating, deadly mystery. It was first described in the mid-19th century, when French physicians linked deaths from muscle spasticity and wastage to shriveled nerve fibers in the spinal column. In the time since, progress on understanding the causes of ALS and related motor neuron diseases—such as spinal muscular atrophy, which, in its severest form, is a fatal disease in children—has been maddeningly slow.
On a gross level, motor neurons, the long nerve cells that control movement, degenerate and die. Patients are typically diagnosed between the ages of 40 and 70, and they rarely survive more than five years. (About 10 percent of patients, including cosmologist Stephen Hawking, have a slowly progressing form of the disease and can survive for decades.) Often, control of the legs goes first, and then paralysis marches upward, eventually shutting down the lungs. In other cases, the face is affected first. The disease leaves the intellect and emotions of patients intact as their bodies wither. "It's a devastating disease," says Bonini, and it affects about 2 in 100,000 people worldwide.
“The field is making progress," Hugo Bellen says. "Every year we make strides toward better understanding. But it's been a very tough nut to crack.”
In 1991, an international team funded by the ALS Association and others, including HHMI, identified a form of ALS that runs in families. By 1993, the team had pinpointed mutations in a gene called SOD1 as responsible for some of these inherited cases. But only a small proportion of ALS cases—perhaps 2 percent—appear to be caused by the inherited SOD1 mutations, leaving researchers scratching their heads as to the cause of the vast majority of cases.
The search for treatments has been nearly fruitless, as well. Just one drug, riluzole (marketed under the brand name Rilutek), is approved to treat ALS, and it extends life by only a few months. A handful of other drugs are in clinical trials, but many more lie abandoned after failing in large studies. In one new treatment approach launched this year in two phase 1 trials, researchers implant nerve or bone marrow stem cells into the spinal columns of ALS patients. The hope is that the stem cells will pump out protective growth factors that rescue or rebuild dying motor neurons, says the leader of one of the trials, Clive Svendsen, director of the Regenerative Medicine Institute at Cedars-Sinai Medical Center in Los Angeles. But it will be years before researchers know whether stem cell therapy helps ALS patients.
Fingering Protein Clumps
"Oh, that's disturbing," Bonini proclaims. She's watching a big-screen monitor that displays microscope images of motor neurons autopsied from an ALS patient. Gitler, operating the microscope, points to the ugly brown smear that caused Bonini's reaction. It's a large clump of protein and it's not where it belongs.
In healthy motor neurons, this protein, TDP-43, accumulates only in the nucleus, where it's required for normal processing of RNA. But in the motor neurons of ALS patients, TDP-43 somehow escapes the nucleus and clumps in the cell body. "It's like a skein of yarn coming out of the nucleus," Gitler says. "It's just really striking. It's a dense aggregate."
In 2006, Penn Medicine neuroscientist Virginia Lee and colleagues reported finding clumps of TDP-43 in the motor neurons of ALS patients and in other nerve cells in patients with frontotemporal dementia, a condition that can cause sudden and baffling deviant behavior. The telltale clumps have also been found in athletes—including former professional football players—who later in life developed ALS-like disease and died. Subsequently, various research groups reported mutations in the TDP-43 gene (also called TARDBP) in families in which multiple members had ALS.
The discovery attracted Bonini's attention. "TDP-43 is probably a big player in different types of neurodegeneration," she says. "Everyone is trying to figure out how it hurts neurons."