Summary: Researchers have identified the enzyme ten-eleven-translocation 1 (TET1) as a critical regulator of myelin repair in the adult brain. The discovery sheds light on age-related decline in remyelination and could influence future approaches to treating neurodegenerative conditions such as multiple sclerosis and Alzheimer’s disease.
Source: CUNY
New evidence indicates that the adult brain retains the capacity to generate new cells in response to injury, physical activity, and cognitive stimulation. Among these cells, glial populations—especially oligodendrocyte progenitor cells—are highly responsive to environmental cues and damage. These progenitors differentiate into oligodendrocytes that produce myelin, the insulating layer around axons that supports metabolic needs and ensures rapid, precise electrical signaling.
However, the formation of new myelin declines with age. This reduced remyelination capability correlates with cognitive and motor declines commonly observed in older adults. Impaired myelin repair is also associated with progressive deterioration in neurodegenerative diseases, including multiple sclerosis and Alzheimer’s disease.
A team from the Neuroscience Initiative at the Advanced Science Research Center at The Graduate Center, CUNY (CUNY ASRC) has identified ten-eleven-translocation 1 (TET1) as a key molecule required for effective myelin repair in adult brains. Their findings, published in Nature Communications, indicate that TET1 modifies DNA in specific glial cells, enabling them to form new functional myelin after injury.
“We designed experiments to identify molecules that could affect brain rejuvenation,” said Sarah Moyon, Ph.D., research assistant professor with the CUNY ASRC Neuroscience Initiative and lead author of the study. The team observed that TET1 levels decline progressively in older mice, and this decline alters DNA modifications needed for proper myelin formation.
Using whole-genome sequencing and bioinformatics, the researchers demonstrated that DNA changes driven by TET1 in young adult mice are essential for healthy communication between cells in the central nervous system and for maintaining normal function. Genetically modified young mice lacking TET1 in myelin-forming glial cells failed to produce functional myelin and displayed deficits resembling those seen in older animals.
“This age-related decrease in TET1 may explain why older individuals have reduced capacity to form new myelin,” said Patrizia Casaccia, founding director of the CUNY ASRC Neuroscience Initiative and the study’s principal investigator. She added that studying how aging affects glial cells both in normal conditions and in neurodegenerative diseases may guide development of therapies to slow disease progression in disorders such as multiple sclerosis and Alzheimer’s.
The discovery also raises the possibility of molecular rejuvenation strategies for aging brains. The authors report ongoing experiments to test whether restoring or increasing TET1 levels in older mice can rescue remyelination capacity and reestablish effective neuro-glial communication. The long-term objective of this work is to promote recovery of cognitive and motor functions in older adults and in patients affected by neurodegenerative diseases.
About this neurology research news
Source: CUNY
Contact: Shawn Rhea – CUNY
Image: The image is in the public domain
Original Research: Open access. “TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice” by Sarah Moyon, Rebecca Frawley, Damien Marechal, Dennis Huang, Katy L. H. Marshall-Phelps, Linde Kegel, Sunniva M. K. Bøstrand, Boguslawa Sadowski, Yong-Hui Jiang, David A. Lyons, Wiebke Möbius & Patrizia Casaccia. Nature Communications.
Abstract
TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice
The molecular mechanisms that govern myelin repair in the adult central nervous system remain incompletely understood. This study identifies DNA hydroxymethylation, catalyzed by the TET family enzyme TET1, as a necessary process for remyelination in young adult mice and as a pathway that becomes defective with age.
Targeted genetic removal of Tet1, either constitutively or inducibly and specifically in oligodendrocyte-lineage cells, reproduces the age-related decline in repair of demyelinated lesions. In contrast, removal of Tet2 did not produce the same effect. Integrated DNA hydroxymethylation mapping and transcriptomic analysis revealed that TET1 regulates genes in adult oligodendrocytes that are involved in neuro‑glial communication, including members of the solute carrier (Slc) gene family.
Among TET1 targets, the Na+/K+/Cl− transporter SLC12A2 showed higher expression in Tet1-overexpressing cells and reduced expression in aged animals or Tet1 knockouts. Both aged mice and Tet1 mutants exhibited impaired myelin repair and structural changes at the axon–myelin interface, such as axo‑myelinic swellings. Complementary studies in zebrafish mutants for slc12a2b also revealed swellings in myelinated central nervous system axons, supporting a conserved role for these transporters in axon–myelin integrity.
Together, these results indicate that TET1-dependent DNA hydroxymethylation is required for effective remyelination in the adult CNS and for maintaining proper axon–myelin interactions.