5 April 2013. Oligodendrocytes are joining astrocytes and microglia as members of a glial syndicate involved in the pathology of amyotrophic lateral sclerosis, according to a paper in the March 31 Nature Neuroscience online. Scientists from Johns Hopkins University in Baltimore, Maryland, report that a cycle of oligodendrocyte death and replacement precedes the onset of motor neuron death and symptoms in ALS model mice. In particular, they noted defects in these myelinating glia in the grey matter of the spinal cord and motor cortex of the mice, and also in people with ALS. The namesake white matter “lateral sclerosis” that results from the degeneration of motor neuron axons is well established, but the damage to myelin in grey matter seen here is a new concept, noted coauthor Jeffrey Rothstein. The work indicates that motor neurons depend on oligodendrocytes not just for insulation, but for their very survival.
“This is particularly exciting because it demonstrates a critical and completely unexpected role for oligodendrocytes,” wrote Brian Popko of the University of Chicago, Illinois, in an e-mail to Alzforum. Popko was not involved in the study. Oligodendrocytes wrap motor neuron axons in an insulating myelin sheath, and they are thought to somehow nourish the neuron as well. If oligodendrocytes die, progenitor cells can proliferate and replace them. This cycle of oligodendrocyte degeneration and renewal is responsible for the relapses and remissions of multiple sclerosis, noted senior author Dwight Bergles. He and Rothstein previously reported that oligodendrocyte progenitors overproliferate and differentiate in mice expressing the mutant human ALS gene superoxide dismutase 1 (SOD1; see ARF related news story on Kang et al., 2010). In the current work, they used BrdU and an inducible green fluorescent protein tag to trace the fate of the oligodendrocytes themselves.
Despite the proliferation of progenitors, the total number of oligodendrocytes in adult mSOD1 animals was normal, discovered joint first author Shin Kang, who worked with Bergles and has since started his own laboratory at Temple University in Philadelphia, Pennsylvania. This suggested that the proliferation occurred in step with oligodendrocyte death, keeping the population steady. When Kang labeled oligodendrocytes present at 30 days of age, he saw the labeled cells survive out to 120 days in control mice, but in animals with mSOD1, more than half of them had disappeared by that time. As the older oligodendrocytes died, new ones took over. While oligodendrocyte generation normally dwindles after the first several weeks of life, the mutants were still turning out abundant newborn oligodendrocytes at two months of age, and the proliferation continued throughout life. However, those replacements were not quite right. They wrapped neurons in misshapen, immature myelin.
This compensatory but dysfunctional oligodendrocyte turnover was particularly apparent in the grey matter of the ventral spinal cord. “There is really a hot spot in the ventral horn, right where the motor neurons are degenerating,” Bergles said. “This is a very early event in the disease.”
Other researchers have shown that astrocytes and microglia fuel ALS progression in experiments where they selectively deleted mSOD1 from those cell types, which extends survival but does not delay onset (Boillée et al., 2006; Yamanaka et al., 2008). In the current study, joint first author Ying Li in Rothstein’s laboratory applied the same technique to the oligodendrocytes. Deleting mSOD1 from them and their progenitors before the mice reached one month old delayed the start of their symptoms by up to four months, Rothstein said. This is a huge effect for these extremely ill animals. However, once the degeneration took hold, it proceeded at its usual pace. “You dramatically change the onset,” said Rothstein. He concluded, “Wow! These cells contribute in some way.”
At this point, the nature of the contribution remains uncertain. While astrocytes and microglia affect disease progression, the results indicate that healthy oligodendrocytes stave off neurodegeneration for a while. One possibility is that oligodendrocytes provide lactate to fuel motor neuron axons. Rothstein’s group previously found that both mouse models and people with ALS are deficient in an oligodendrocyte transporter that expels lactate (see ARF related news story on Lee et al., 2012). The grey matter might be a place where axons are particularly dependent on oligodendrocyte-provided nutrients, speculated Bruce Trapp of the Cleveland Clinic in Ohio, who was not involved with the paper.
Li confirmed that oligodendrocytes play some kind of role in human ALS pathology. In postmortem tissue, she observed less myelin in the ventral horn and motor cortex grey matter of people who had ALS than did controls. If these grey matter defects indeed occur early in disease, they might be visible on magnetic resonance imaging and serve as a marker for disease progression, Rothstein speculated.
ALS researchers have not spent much time considering how to help oligodendrocytes help neurons—but multiple sclerosis researchers have. Anti-inflammatories are well established in the MS field. Medications to protect or repair neurons are “considered the future of MS therapeutics,” said Trapp, who works on MS. Most of these treatment ideas are in preclinical stages. “It is possible that some of the same therapeutic strategies might have benefit in ALS,” Bergles suggested.—Amber Dance.
Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE. Degeneration and impaired regeneration of grey matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci. 2013 Mar 31. Abstract