National Geographic

Supporting the Support Cells in Lou Gehrig’s Disease

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.

There are 10 Comments. Add Yours.

  1. Benjamin
    March 31, 2013

    Currently watching my brother-in-law fight ALS. To be completely honest it’s not so much a fight as ALS is very quickly destroying him. It’s only been a few months after being diagnosed and already preparing for a feeding tube being implanted. Whatever these people can do to possibly stop this from happening to others in the future, please do it. Our family holds and takes part in so many ALS fundraisers every year, and it gets harder and harder to attend knowing right now the people who struggle with this literally have no hope other than some kind of miracle. I’m sure no one who is researching ALS is reading his, but if you are, thank you for all your efforts. From the bottom of my heart, THANK YOU.

  2. Benjamin
    April 1, 2013

    *I meant to say “every month” not “every year”. Feels like years, though.

  3. Virginia Hughes
    April 1, 2013

    Thanks so much for sharing that, Benjamin. I wish you and your family the best during what must be an emotionally and physically exhausting time.

  4. Patty
    April 1, 2013

    This is so good to hear. Any clues that are found get us one step closer to a treatment and potential cure. I was diagnosed with ALS last fall. They tell me it’s progressing slowly but I’m not so sure. I am seen every 3 months at the UCSD Clinic and have donated blood to be used in current and future research. Here’s hoping there’s a cure on the horizon for future ALS patients.

  5. Lynn Lee
    April 1, 2013

    I was diagnosed 11-04-2010. I guess I’m progressing slowly but wish to be done with it. For an athletic, independent person, I hate having to ask for help for everything and I’m going to run out of money. I’m usually more upbeat … I know God has a plan!

  6. Lexi Shanklin
    April 2, 2013

    The Other Brain by R. Douglas Fields is a great resource on glia’s role in neurodegen diseases and psychiatric illnesses.

  7. Mrs. Adele Edwards
    April 25, 2013

    I was diagnosed in February 2012. Up until that time I was faithfully attending Bikram Yoga 5-6 times a week. When I was first diagnosed my muscle tone was so good (from yoga) I needed to see the head neurologist in B.C. before it was diagnosed for sure. For that I will be eternally grateful. The ALS of B.C. pays for everything! So far, my legs and balance are affected so I continue to live only much, much slower!

  8. Gabriel E, Vando
    April 25, 2013

    Theres is very little hope, Why? Because there are so few patients with Lou Gehrig’s desease that the big pharmaceuticals will noit invest monies in finding a cure, its not profitable…bad news.. I doubt that a single humanitarian investigator would have the economical means in order to adequately and efficiently contribute to solving this desease, sorry about that.

  9. liza
    April 27, 2013

    Hard work, more optimism and everything will be great.very interesting article.

  10. Bohemian hippie
    June 3, 2013

    My best friend is dying a slow and agonizing death before my eyes and it breaks my heart. Just two years ago we talked about living to drive our children and grandchildren nuts. The disease has robbed her of ever holding her grandchildren and now she won’t be able to watch them grow up. I am so sad and angry about her condition.

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