Myelin molecule transports sustenance to neurons
The myelin that encases axons is best known as an insulator, but new research shows that it doesn’t just envelop nerves—it also nourishes them. Cells called oligodendrocytes, whose membranes form the myelin sheath, transport fuel to axons with a special shuttling molecule, according to a study published online 11 July in Nature. Without this carrier in oligodendrocytes, axons degenerate and neurons die.
The new work suggests that “demyelination may have much more prominent effects on energy imbalance than we might have thought,” says Bruce Trapp, a neuroscientist at the Lerner Research Institute at the Cleveland Clinic in Ohio.
Many neurodegenerative diseases cause myelin to disintegrate, leaving axons bare and slowing signal conductance. For years, however, researchers have suspected that damage to this fatty coating also leaves neurons bereft of power that it normally provides. Most cells—including neurons—use glucose as their primary fuel supply, but this report, along with another paper published earlier this year (Fünfschilling et al., 2012), shows that oligodendrocytes directly nourish axons with an alternative source for making ATP: lactate. In that work, Klaus-Armin Nave, a neuroscientist at the Max Planck Institute for Experimental Medicine in Göttingen, Germany, showed that oligodendrocytes produce and release lactate, thus bathing axons in an energy-rich soup.
The current study, led by Jeffrey D. Rothstein, a neuroscientist at Johns Hopkins University, went a step further to show that a protein called MCT1 transports lactate out of oligodendrocytes into the space between their cell membranes and those of axons. The neurons likely use a different transporter molecule to shuttle the lactate inside, Rothstein says.
“The two papers come to very similar conclusions based on two different approaches,” Nave says: Oligodendrocytes are feeding axons lactate, which they need to survive.
Previous work had shown that MCT1 moves lactate across cell membranes and that the protein is the predominant transporter in the brain’s glial cells, which do not conduct electrical messages, as nerve cells do, but support neurons in various ways. Rothstein and his colleagues wanted to learn more about MCT1’s behavior in live animals; they strongly suspected that glial cells called astrocytes would play a dominant role, because these cells manufacture it in culture. The scientists created a strain of genetically engineered mice in which MCT1 carries a red fluorescent protein tag. Then they bred these animals with one of two other mouse strains in which specific proteins made by either oligodendrocytes or astrocytes were labeled with green fluorescent protein. By zeroing in on cells that carried both colored tags, they discovered that oligodendrocytes produced MCT1, but astrocytes didn’t, Rothstein says—a surprise, given the observations in cultured cells.
Next, Rothstein and his colleagues tested whether neurons could survive without MCT1. When they turned off activity of the MCT1 gene or applied a chemical that blocks the protein’s activity in slices of spinal cord grown in a culture dish, a third of the neurons died. However, the researchers could rescue the cells by adding lactate to the media. Using a different technique, the team then dampened the MCT1 gene’s ability to generate protein in the brain of a living mouse, which killed off half the neurons near the injection site. “Without MCT1, neurons suffer and die,” Rothstein says.
MCT1 shutdown did not harm oligodendrocytes in any obvious way, either in culture or in vivo. Much of the myelin remained plush, as indicated by direct visualization of the substance. Together, the observations suggest that an apparently intact myelin sheath doesn’t necessarily signify health. Given that axons can survive for lengthy periods with thin myelin, Rothstein concludes that neurons need the substances that oligodendrocytes produce—more than the insulation they provide—to survive. Conversely, even if myelin becomes very thin, the surviving oligodendrocytes might still provide nutrient support at the axon membrane.
Finally, the researchers investigated the transporter’s role in the pathology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Motor cortex from patients with ALS contained half the amount of MCT1 as in healthy control tissue. That drop was undetectable in the frontal cortex, which is not affected in ALS. Likewise, MCT1 was reduced in brains of early and late stages of mice with a commonly used model of ALS.
The research community has focused on insulation as the primary function of oligodendrocytes, yet this newly discovered axon-feeding mechanism “is a fundamental biological property” of the cells, Rothstein says. The findings, he adds, might well apply to any neurodegenerative disease.
By that reasoning, MCT1 could serve as a target for therapeutic strategies that prevent neurodegeneration, Rothstein says. And because MCT1 lives in the oligodendrocyte membrane that contacts neurons directly, thinly myelinated axons might still benefit from such treatments.
MCT1 has not emerged from any MS genetic-association studies, but it might misbehave in the disease through the action of some kind of regulator molecule, Trapp says. Regardless of any potential link between the transporter and MS, he says, the new findings suggest that MS researchers should turn their attention to how oligodendrocytes supply neurons with energy.
Key open questions
- Are MCT1 quantities reduced in brain tissue from MS patients?
- Is MCT1 activity reduced in brains of animals with diseases that mimic aspects of MS?
- Could lactate-supplementation therapies potentially support demyelinated axons?
Thumbnail image on landing page. "Neuron with oligodendrocyte and myelin sheath," 2010. Released into the public domain.
Neuronal activity demands large amounts of energy and previous work suggests that astrocytes can provide substrates that help power neurons. This paper extends that concept to another type of glial cell, oligodendrocytes, which make the myelin sheaths around axons. Nave’s group genetically knocked out a key portion of the mitochondrial electron transport chain in oligodendrocytes, thus destroying the cells’ usual way of extracting energy. In this situation, the oligodendrocytes utilized a different metabolic pathway for deriving energy, albeit inefficiently; its end product, lactate (which still contains high-energy electrons), passed to the underlying nerve cell. The work suggests a mechanism by which oligodendrocytes support nerve-cell survival and might help explain why nerve cells deteriorate when the myelin sheath is attacked in MS.