Scientists Discover Enzyme Needed for Activating Myelin Repair
The enzyme TET1, which is progressively lost with age, is essential to activate genes needed to repair myelin — the sheath around nerve cells that is damaged in people with multiple sclerosis (MS) — a study in mice has found.
The scientists said their discovery supports further research to find ways to reverse TET1 decline, repair myelin damage, and slow MS progression.
“Our findings suggest that TET1 is required for adult myelin repair,” the team wrote.
The study, “TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice,” was published in the journal Nature Communications.
The formation of new myelin, the protective coat that surrounds nerve fibers or axons, is vital for repairing damaged or lost myelin. However, this repair process is impaired in several neurological diseases, including MS.
Myelin itself is a specialized membrane of cells called oligodendrocytes — a type of glial cell that does not produce electrical impulses but acts to support and protect nerve cells (neurons) — which arise from oligodendrocyte progenitor cells (OPCs).
The transition from OPCs to oligodendrocytes to repair myelin can be affected by many external factors, including diseases and aging. As people age, less myelin is formed, leading to age-related cognitive and motor decline. This is especially apparent among those with neurodegenerative diseases such as MS or Alzheimer’s.
One biological process implicated in the transition that gives control of the OPC to oligodendrocytes is epigenetics. This is the chemical modification of DNA and DNA-related proteins that regulate the activity of genes.
DNA methylation is an epigenetic modification in which methyl groups are added to DNA to suppress gene activity. In contrast, DNA hydroxymethylation acts to add hydroxymethyl groups to DNA to activate gene activity. DNA is hydroxymethylated by a family of enzymes called TETs, which are found at high levels in neurons and glial cells.
While DNA methylation has been reported to play a role in myelin formation in developing fetuses, it only plays a minor role in the adult OPC-to-oligodendrocyte transition during myelin repair. However, whether DNA hydroxymethylation is involved in myelin repair in adult brains is unknown.
To find out, scientists based at the Neuroscience Initiative Advanced Science Research Center at the City University of New York (CUNY ASRC) used mouse and zebrafish models to learn more about the role of DNA hydroxymethylation in age-related myelin repair.
“We designed experiments to identify molecules that could affect brain rejuvenation,” Sarah Moyon, PhD, the study’s lead author and a research assistant professor with the CUNY ASRC Neuroscience Initiative, said in a press release.
Given that adult OPC function is to repair myelin in response to injury, the team induced demyelination in the spinal cord of young and old mice with a chemical called LPC. Myelin was efficiently repaired in young mice after the LPC injection. But it remained impaired in aged mice, with fewer remyelinated axons.
The successful myelin repair in young mice was proceeded by an increase in OPCs with high levels of DNA hydroxymethylation. In contrast, in the old mice, there was a lower amount of OPCs with enhanced DNA hydroxymethylation — even though the numbers of OPCs remained constant between young and old mice.
“Together, these data support an overall age-dependent decline of DNA hydroxymethylation and remyelination,” the team wrote.
DNA is hydroxymethylated by the TET family of enzymes, which includes TET1, TET2, and TET3. Experiments confirmed that TET1 enzyme levels — but not those of TET2 or TET3 — declined with age. The age-related differences in TET1 levels, but not TET2, persisted in the injured adult spinal cord during myelin repair.
To support these findings, special mice were bred that lacked the TET1 enzyme. These mice did not differ in body size, weight, or survival, or show any obvious motor difficulties compared with control mice, the researchers reported. In addition, the loss of TET1 did not impact adult myelination during mouse development.
However, in response to LPC injury, adult mice without the TET1 enzyme showed defective DNA hydroxymethylation and impaired myelin repair compared with controls. Furthermore, microscope analysis found fewer remyelinated axons in TET1 mutant mice after injury, which supported “the inability of adult OPCs to reach high levels of DNA hydroxymethylation, as seen in old mice and in the Tet1 constitutive mutants,” the researchers wrote.
Since DNA hydroxymethylation controls gene activity, the team set out to identify which genes may be modified during myelin repair. The team detected 5,583 genes with hydroxymethylated regions, and most of these genes were hydroxymethylated during the transition from adult OPCs to oligodendrocytes. TET1 was then shown to be essential for activating genes associated with myelin repair after demyelination in adult mice following LPC injury.
“These results define TET1 function as dispensable for developmental myelination, but essential for the activation of a transcriptional program associated with myelin repair after demyelination,” the researchers wrote.
As a proof-of-principle, one of the TET1-target genes — Slc12a2 — was selected for examination. This gene encodes for a protein channel called SLC12A2 that transports sodium, potassium, and chloride ions across nerve cell membranes. SLC12A2 regulates the responses in OPCs to nerve signals and is enriched in newly formed oligodendrocytes.
The activity of Slc12a2 was shown to be dependent on TET1 and declined along with the enzyme in an age-dependent manner. Slc12a2 activity was higher during myelin repair in young mice, but not during inefficient remyelination in older mice — due to the lower TET1 levels and reduced DNA hydroxymethylation.
“We found that TET1 levels progressively decline in older mice, and with that, DNA can no longer be properly modified to guarantee the formation of functional myelin,” added Moyon.
Additionally, SLC12A2 was located at the interface between axons and myelin in young mice but also found in the inflamed axons-myelin interface in older mice. Those findings “suggested the importance of TET1-target genes in regulating fluid accumulation at this interface,” the researchers added.
Finally, to support these results, the scientists used a zebrafish model with a mutation in the bred slc12a2b gene — the zebrafish counterpart of the Slc12a2 gene. While myelin normally formed in these mutant fish at an early age, localized swelling appeared in individual myelin sheaths over time.
“Our study defines the major role of TET1-mediated DNA hydroxymethylation, as a regulator of gene expression during myelin repair, which becomes defective with aging,” the investigators concluded.
“Worth noting, in this respect is the dramatic downregulation of the TET enzymes detected in post-mortem brain tissue from multiple sclerosis patients, thereby highlighting the overall translational potential of our findings,” they added.
“This newly identified age-related decline in TET1 may account for the inability of older individuals to form new myelin,” said Patrizia Casaccia, MD, PhD, the study’s lead author and a professor at the ASRC.
“I believe that studying the effect of aging in glial cells in normal conditions and in individuals with neurodegenerative diseases will ultimately help us design better therapeutic strategies to slow the progression of devastating diseases like multiple sclerosis and Alzheimer’s,” Casaccia said.