ARTICLE IN BRIEF
DR. JEFFREY D. ROTHSTEIN: “This research is teaching us that oligodendroglia have a predominant and fundamental role in metabolic support to neurons in grey and axons in white matter. When they don't do what they're supposed to do, the axons degenerate and that causes neurons to die.”
Investigators report that a lactate transporter abundant in oligodendroglia seems to contribute to neurodegeneration, particularly in amyotrophic lateral sclerosis.
In studying the fundamental relationships between glia and neurons, a team of researchers at Johns Hopkins University unexpectedly provided new evidence that oligodendroglia are critically necessary to support axons independent of their role in myelination. They then decided to see whether these support cells could play a role in the death of motor neurons and amyotrophic lateral sclerosis (ALS). Surprisingly, they did.
Reporting in the July 12 online edition of Nature, Jeffrey D. Rothstein, MD, PhD, the John W. Griffin director of the Brain Science Institute and professor of neurology and neuroscience and director of the Robert Packard Center for ALS Research, and his colleagues found that the most abundant lactate transporter in the CNS — 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.
“Once we found that the MCT1 protein was down in ALS gray matter, the question was: is it relevant to the disease?” Dr. Rothstein said.
STUDY METHODS
The investigators used a variety of methods to knock down or completely knock out MCT1 expression and, when they did, neurons died. But many cell types could possibly express MCT1 so they needed better tools to figure out what was really going on. They produced two lines of bacterial artificial chromosome (BAC) transgenic mice carrying a red fluorescent reporter for the location and expression of MCT1 messenger RNA in the CNS and peripheral organs. The BAC mice were crossed with another BAC mouse that expressed a green fluorescent protein driven by oligodendroglia and astrocytes. Previously the Rothstein lab was the first to show ALS has been associated with abnormalities in astrocytes, and actually began this project, they thought, to understand astrocyte biology in ALS.
Youngjin Lee, PhD, a post-doctoral student in the lab, noticed something very unusual. No astrocytes were lighting up in the studies to find MCT1. Instead, it was the oligodendroglia that was shining bright. On closer inspection and with the help of a sensitive cell sorter, they found that oligodendroglia is enriched with MCT1, not the astrocytes. When they turned off MCT1, they cut off the lactate transporter's ability to shuttle energy from the axon to the neuron.
Their studies in vitro showed that neuron survival is dependent on oligodendroglial MCT1. They took spinal cord cultures treated with antisense oligonucleotides or a specific MCT1 transport inhibitor and found that down-regulation or inhibition of MCT1 produced neuronal death. After three weeks of treatment, a third of the motor neurons had died. The loss of MCT1 did not itself kill the oligodendroglia; rather this oligodendroglial deficit led to neuronal death, including motor neurons, due to the lack of lactate transport from oligodendroglial to neurons, and this could be prevented 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.
DR. STANLEY H. APPEL: “This is an elegant and seminal finding. Clearly, there is dialogue between oligodendroglia and axons and the transcription of MCT1 plays an important role. Oligodendroglia are important and contribute to motor neuron health through axons.”
He added that it is possible that this mechanism is involved with other neurodegenerative conditions. In general, any injury to oligodendroglia could be a source for neuronal degeneration. For example, chronic axonal degeneration now widely understood to occur in multiple sclerosis could reflect damage to this pathway.
The researchers also looked at an animal model with reduced levels of MCT1 and identified significant and widespread axonal degeneration. They found deficits in MCT1 in ALS patients, as well. Specifically, the motor cortex of patients, compared with healthy control brains, showed a greater than 50 percent decline in MCT1 expression (p < 0.01). This reduction was not seen in other areas of the frontal cortex that were not affected by the disease, Dr. Rothstein said.
“This research is teaching us that oligodendroglia have a predominant and fundamental role in metabolic support to neurons in grey and axons in white matter. When they don't do what they're supposed to do, the axons degenerate and that causes neurons to die.”
“Our results suggest that oligodendroglia support of axons, through MCT1-based transport of lactate (or pyruvate) is crucial for maintaining axon function and neuron survival,” the scientists wrote in the Nature paper. It “seems to be a fundamental property of oligodendroglia.”
So far, Dr. Rothstein said that they see a loss of MCT1 but plenty of oligodendrocytes, which could explain why no one has picked up a problem before now. “The implication is that there is some kind of injury to oligos but we really don't know what is going on. What we do know is that MCT1 is critical for the survival of neurons.”
The Hopkins scientists added that they are now conducting experiments to test “whether MCT1 down-regulation is specific for ALS and whether MCT1 up-regulation or transplantation of oligodendroglia can prolong survival in ALS mouse models.”
EXPERTS WEIGH IN
“This is an elegant and seminal finding,” said Stanley H. Appel, MD, the Edwards distinguished endowed chair for ALS and director of the Methodist Neurological Institute and chair in the department of neurology. “Clearly, there is dialogue between oligodendroglia and axons and the transcription of MCT1 plays an important role. Oligodendroglia are important and contribute to motor neuron health through axons.”
Other groups have shown that astrocytes produce lactate to support neurons. “But maybe oligodendrocytes are more important to this process,” Dr. Appel said.
Would adding lactate be sufficient to alter the pathology in ALS? “We just don't know yet how significant a player the oligodendroglia will be,” he added. “There are now many cell types that are involved in ALS, including macrophages and astrocytes. It follows that all of this [pathology] could be the consequence of impaired neuronal metabolism.”
Steven A. Goldman, MD, PhD, Rykenboer professor of neurology and co-director of the Center for Translational Neuromedicine at the University of Rochester, said that astrocytes and oligodendroglia interact in metabolism. “But it took a new way of looking at things to find that ALS may be linked to an oligodendroglia deficit,” he said. “It is an interesting new perspective.”
“These are early studies and it remains an open question whether this will ultimately help patients,” he added.
The study was supported by grants from the NIH, the Muscular Dystrophy Association, the Packard Center for ALS, Human Frontier Science Program, Swiss National Science Foundation, and the Biaggi and Puccini Foundations.
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How did investigators come to discover that oligodendroglia play a role in neurodegeneration? Listen here as Jeffrey D. Rothstein, MD, PhD, lead investigator of the July 12 online paper in Nature, describes the back-story of how researchers made the surprise discovery — and where they're going next with it http://bit.ly/rCBryX.
