In 1874, French neurologist Jean-Martin Charcot published a series of papers describing a horrible nerve disease. It begins with weakness, stiffness, and spasms in the arms and legs. Over the course of about a year, muscles stop working, and with them goes the ability to walk, stand, and speak. Then the tongue and lips stiffen. The mouth gets stuck partway open, accentuating laugh lines and giving “an appearance of weeping,” Charcot wrote. “Finally, the vagus nerve is affected with grave difficulty breathing, leading to death of a person already so weakened by insufficient nourishment.”
Charcot was also an expert pathologist. After performing autopsies on several of these patients, he named their disease amyotrophic lateral sclerosis: muscle atrophy (amyotrophic) with scarring (sclerosis) in part of the (lateral) spinal cord. The scarring came from the death of motor neurons, large cells in the spinal cord whose long branches reach out to muscles and control their contractions.
More than a century has passed, and still the only way to definitively diagnose ALS — known as Lou Gehrig’s disease here in the U.S. and as Charcot disease in France — is with an autopsy showing the widespread disappearance of motor neurons in the spinal cord and the brain. It’s not surprising, then, that the vast majority of research on the roots of ALS has focused on motor neurons. But in the past few years, scientists have found hints that several types of glia, the under-appreciated cells typically described as “support cells” for neurons, may also be cellular culprits in the disease.
“What’s maybe a misnomer in the field is that people think that just because the motor neurons die, that that’s the source of disease,” says Dwight Bergles, a professor of neuroscience at Johns Hopkins University. “But there are multiple cell types that contribute.”
In today’s issue of Nature Neuroscience, Bergles and his colleagues find that oligodendrocytes — glia that wrap around the branches of motor neurons, creating a fatty sheath that gives the neuron energy and insulates its electrical messages — die in a mouse model of ALS even before the animals show symptoms of the disease. According to Bergles and others, the findings point to a possible new treatment strategy for many types of neurodegenerative disease: support the support cells.
“Neurons and glial cells have this intimate relationship in the nervous system, and neurons are absolutely dependent on glial cells for support,” Bergles says. “So obviously if you somehow could preserve the functions of these support cells, that could have benefit.”
Like so many scientific discoveries, this one began with a bit of serendipity. A few years ago, while working as a postdoc at the Vollum Institute in Portland, Oregon, Bergles was studying the normal activity of stem cells that give rise to oligodendrocytes. In a separate project, he was also looking at a common mouse model of ALS. “One day, just on a lark, we said hey, why don’t we look at the cells in the ALS tissue?” he recalls.
They found that in adult ALS mice, these progenitors, called NG2+ cells, divide rapidly in the same regions of spinal cord where motor neurons die. What’s more, as the disease progresses, the NG2+ cells make more and more oligodendrocytes. “We knew this was really unusual in an adult animal, so we thought there must be something happening to oligodendrocytes in this disease,” Bergles says.
The new study extends those findings in the same animal model, mice that make way too much of a mutant protein called SOD1. A small number of people with rare familial forms of ALS carry mutations in the SOD1 gene, and the SOD1 mice have several characteristic features of the disease, including muscle paralysis, motor neuron degeneration and early death.
Previous studies by Bergles’s colleague Don Cleveland of the University of California San Diego had found that removing the mutant SOD1 protein from specific types of glial cells, including microglia and astrocytes, slows the progression of disease. This suggests that when the gene’s function is messed up in these glial cells, it somehow exacerbates the disease. In the new study, Bergles and Cleveland found the same thing for oligodendrocytes. They report that in ALS mice, oligodendrocytes are damaged even before the mouse shows overt symptoms. What’s more, removing the mutant protein only from NG2+ cells significantly delays the onset of disease and prolongs the animals’ survival.
Like all studies that use this popular mouse model (or any mouse model), it’s unclear whether the findings extend to people with ALS. Bergles’s team showed that oligodendrocytes look abnormal in postmortem brain and spinal cord tissues from of people who died of ALS. Still, because glia are known to react to all sorts of problems in the brain, it’s hard to tease out cause and effect.
“It’s a very elegant and potentially interesting observation but for the moment it’s just correlative,” notes Serge Przedborski, a professor of neurology at Columbia University who has studied the role of astrocytes in the SOD1 model. Although the study doesn’t reveal any particular mechanism behind the oligodendrocyte oddities, Przedborski notes that a study published last year by Jeff Rothstein, another one of the new paper’s authors, could offer a clue.
In that work, Rothstein’s group found that oligodendrocytes hold molecules that transport lactate, a cellular energy source, and that disturbing these transporters leads to neuron death. The researchers also found that people with ALS and SOD1 mice lack these transporters. All of this suggests that oligodendrocytes are a key source of energy for neurons and that oligodendrocyte damage contributes to ALS progression.
If that’s the case, then the question of cause and effect might not matter in the development of treatments.
“For many, many years we all in the field of neurodegeneration have unfortunately looked at it from a very neuronal-centric view,” Przedborski says. “But neurons do not live or die in isolation. They’re surrounded by all these non-neuronal cells, and these cells are playing a key role, even before the disease starts.” This is most likely the case not only for ALS, but for Parkinson’s, Alzheimer’s, Huntington’s, and “any other neurodegenerative disorder you can think of,” he says.
It might also mean that the ALS field can look to other diseases for insights on treatment. Multiple sclerosis (MS), for example, stems from the destruction of oligodendrocytes, and several research groups have been developing MS drugs that promote the survival of oligodendrocytes. “So the thought now is that we could take some of the knowledge gained in the MS field and apply it to ALS,” Bergles says.
Here’s hoping. The treatment arsenal for ALS is empty. And the disease’s prognosis hasn’t much changed since Charcot described it 139 years ago. “As far as I know, there is no case in which all the symptoms occurred and a cure followed,” Charcot wrote. “Is this an absolute block? Only the future will tell.”
For an interesting description of Charcot’s work on ALS, see this 2001 commentary by Columbia University neurologist Lewis Rowland.
Motor neuron image from Van Damme et al., PNAS, 2007.