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Moving Forward on a New Therapeutic Target — Oligodendrocytes — for ALS

Talan, Jamie

doi: 10.1097/01.NT.0000430853.67226.3e
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Investigators used a novel technique to selectively remove mutant superoxide dismutase 1 from oligodendroglia in a mouse model of amyotrophic lateral sclerosis and found it delayed onset of disease by several months, and the mice lived longer.

Scientists at Johns Hopkins University School of Medicine have discovered that oligodendrocytes have an important role in amyotrophic lateral sclerosis (ALS) and targeting these cells could offer a novel strategy to keep axons and motor neurons healthier over a longer period of time.

The study, reported in the Mar. 31 online edition of Nature Neuroscience, suggests that oligodendrocyte progenitors — NG2+ cells — are going through an enhanced proliferation and differentiation very early on in the experimental ALS mouse model — superoxide dismutase 1 (SOD1)-G93A — although the cells never make the transition into mature myelin-making and neuron-supporting cells. The impaired, demyelinated oligodendrocytes are in the gray matter of the motor cortex and spinal cord in the SOD1-G93A mouse. The damaged NG2+ cells appear before the onset of disease.

Once the investigators identified the oligodendrocytes as a player in the disease process, they decided to test whether the dysfunctional support cells were important to the pathogenesis of ALS. They used a technique developed by Don Cleveland, PhD — a professor of medicine, neuroscience and cellular and molecular medicine at the University of California, San Diego, and director of the laboratory of cell biology — to selectively remove mutant SOD1 from oligodendroglia.

The onset of the disease was delayed by at least four months, they reported, and the animals lived longer. Dr. Cleveland, who developed the mice to study astrocytes and microglia, is a co-author of the Nature Neuroscience paper.

While a lot more work needs to be done to understand oligodendrocyte dysfunction in ALS, the scientists, led by Jeffrey D. Rothstein, MD, PhD — the John W. Griffin director of the Brain Science Institute, professor of neurology and neuroscience, and director of the Robert Packard Center for ALS Research — say the studies support the idea that the impaired oligodendrocytes “enhance the vulnerability of motor neurons and accelerate the disease.”

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The investigators learned from earlier work that NG2+ cells were massively proliferating in the SOD1 mutant mice. The big question was why. What were the NG2+ cells doing? Were they responding to a death signal? Were they becoming oligodendrocytes? And was this something unique to ALS mice? Could there be a similar pathology in patients as well?

To attempt to answer these questions, the investigators used the receptor for green fluorescent protein to tag NG2+ cells in the gray matter, which enabled them to track the cells over time. NG2+ cells are abundant in the brain, making up about 8 percent of the cell population. They normally turn into oligodendrocytes, which work with axons to make myelin and provide metabolic support to neurons.

At first blush, it looked like there were normal numbers of oligodendrocytes in the spinal cord. But when they looked more closely they could see that the green oligodendrocytes were not functioning normally. They were not myelinating. This led to progressive demyelination in the gray matter. Dr. Rothstein said that they began seeing injured cells by about two months, at least six months before the first signs of disease.

Removing the mutant SOD1 from the oligodendrocytes kept about half the new oligodendrocytes healthy, said Dr. Rothstein. “And that was enough to push back the disease. It was a huge effect.”

The same pattern of injury was identified in the gray tissue culled from brain tissue from 48 ALS patients, both sporadic and familial cases. Dr. Rothstein said that at least 50 percent of the patient samples showed some injury to oligodendrocytes in the gray matter. They used a blue stain to tag the myelin in gray matter and they saw “big patches where there was no staining for myelin,” Dr. Rothstein added.



He said that they have no idea yet why the oligodendrocytes are dying or why it selectively impacts motor neurons. Earlier work taught them how oligodendrocytes support neurons. In a paper published last year in Nature, they reported that the most abundant lactate transporter in the central nervous system — monocarboxylate transporter 1 (MCT1) — is in plentiful supply in oligodendroglia (as an alternate energy source) and loss or damage to the transporter leads to axon damage and neuronal loss. When the scientists looked to their mouse models and to samples from tissue from deceased ALS patients they were surprised to find that the MCT1 was significantly reduced in number.

The loss of MCT1 did not itself kill the oligodendroglia, rather this oligodendroglial deficit led to death of neurons, including motor neurons, due to lack of lactate transport from oligodendroglia to neurons. They were able to prevent motor neuron death by adding lactate back to the medium. Dr. Rothstein said that they confirmed that the motor neuron death was due to reduced lactate release from oligodendroglia.

“These findings open up broad new avenues for investigation,” said Dr. Rothstein, who collaborated with Dwight Bergles, PhD, a professor of neuroscience at Johns Hopkins, on the latest studies. At present, there is no way to monitor motor neurons in the brain and spinal cord for injury but scanning devices that image myelin in gray matter are now in development. One possible treatment strategy might be to populate gray matter in ALS patients with NG2+ cells and push them to differentiate into healthy oligodendrocytes.

“This biology of oligodendrocytes would not have been expected in neurodegenerative disease,” Dr. Rothstein added.

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“The findings certainly strengthen the argument that oligodendrocyte pathology is contributing to ALS,” said Steven A. Goldman, MD, PhD, Rykenboer professor of neurology and co-director of the Center for Translational Neuromedicine at the University of Rochester, who was not involved in the study. “It will be important to confirm that the oligodendrocyte pathology exists in other ALS animal models. I would be optimistic that this will be a generally conserved mechanism for ALS pathogenesis.”

“They don't know the mechanism so far. Oligodendrocytes receive synaptic input,” he said. “It's possible that the neuronal input is deranged and leaky and that this leads to the oligodendrocyte dysfunction. It's hard to know what's cause and what's effect. There may be pathology in many cell types. Defining the upstream causality remains to be seen.”

“The findings reinforce the fact that if you interfere with the nutritional support of axons you will get into trouble,” added Stanley H. Appel, MD, the Edwards distinguished endowed chair for ALS and director of the Methodist Neurological Institute and chair of the department of neurology. “What causes the oligodendroglial dysfunction is a key question.”



Dr. Appel contends that there may well be an immune-mediated inflammatory effect early in the disease, and that may lead to damaged oligodendrocytes. He sees many similarities between multiple sclerosis and ALS. “If we are right, then the kinds of therapies that can prevent demyelination in multiple sclerosis may be applicable to ALS,” he said.

Ben Barres, MD, PhD, a glial expert and chair of neurobiology and professor of neurobiology, developmental biology, and neurology at Stanford University, said he was “surprised by the finding because to my knowledge oligodendrocyte degeneration has not been previously found to be a feature of human ALS. However, their findings certainly raise the possibility that oligodendrocyte or astrocyte abnormalities can trigger neurodegeneration in some or all ALS or other kinds of neurodegenerative disorders.

“I think that this is very important work that raises many new questions about why oligodendrocytes are dying in the mouse model of ALS, and whether their death is an important driver of motor neuron death in this mouse model as well as in human ALS,” Dr. Barres added.

Klaus Armin-Nave PhD, a professor of molecular biology and director at the Max Planck Institute for Experimental Medicine in Göttingen, Germany, said: “This now speaks strongly also for a primary role of oligodendrocytes in ALS pathogenesis.”

The paper also demonstrates with the help of Don Cleveland's mice that removal of the mutant ALS SOD1 transgene selectively from oligodendrocytes ameliorates the disease course quite a bit, he said, adding: “The relationship between these two mechanisms (or whether it is only one disease mechanisms with two aspects) remains to be sorted out.”

Bruce Trapp, PhD, an expert in multiple sclerosis, said that the autopsy data also “supports their hypothesis that myelin is involved. If so, oligodendrocytes could be a target for therapies. “It may be part of the story but not the whole story,” Dr. Trapp, who is chair of the department of neurosciences at the Lerner Research Institute in Cleveland, OH, added. “But even fixing part of the story can impact the course of the disease. We could think about developing a drug to replace missing or altered oligodendrocytes or precursors. Or maybe we can develop a therapy that fools the axon into thinking it is myelinated.”

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•. Kang SH, Li Y, Bergles DE, et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 2013; E-pub 2013 Mar 31.
    •. Lee Y, Morrison BM, Rothstein JD, et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 2012; 487(7408):443–448.
      •. Vande Velde C, McDonald KK, Cleveland DW, et al. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS One 2011;6(7):e22031. E-pub 2011 Jul 11.
        •. Neurology Today. Oligodendroglia found to play a role in motor neuron death and ALS:
          •. Neurology Today archive on ALS:
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