Progressive decline in myelin—the pliable casing of glial cells that wrap around long neural projections providing metabolic support and facilitating electrical transmission—is linked to cognitive and motor deficits in older people. Myelin formation is also impaired in patients with multiple sclerosis, Alzheimer’s and other neurodegenerative diseases.
A new study published in Nature Communications identifies an enzyme called ten-eleven-translocation 1 (TET1) as a necessary molecule that modifies DNA in specific glial cells in adult brains so that they can form new myelin in response to injury.
This discovery can have important implications for molecular rejuvenation of aging brains in healthy individuals and for recovering cognitive and motor functions in older people and in patients with neurodegenerative diseases.
Evidence reported in the article “TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice” by scientists from the Neuroscience Initiative team at the Advanced Science Research Center (ASRC) at The Graduate Center, City University of New York (CUNY), shows that the TET1 catalyzed DNA modification that functions fine in young mice but is compromised in old mice is hydroxymethylation. This replaces the hydrogen atom at the fifth position in the base cytosine by a hydroxymethyl group and is a key epigenetic regulator.
“We designed experiments to identify molecules that could affect brain rejuvenation,” says Sarah Moyon, PhD, research assistant professor with the CUNY ASRC Neuroscience Initiative and the study’s lead author. “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.”
Patrizia Casaccia, PhD, founding director of the CUNY ASRC Neuroscience Initiative, a professor of biology and biochemistry at The Graduate Center, CUNY, and the study’s primary investigator says, “We adopted several approaches, from genome wide transcriptomics and epigenomic analysis to models of demyelination and mouse genetics, to understand how TET1 modifies gene expression in oligodendroglial lineage cells. We used a newly developed method—reduced representation hydroxymethylation profiling—that allowed us to precisely map a recently discovered DNA modification called hydroxymethylation.”
The authors show TET1 catalyzed DNA hydroxylation targets genes that regulate a healthy dialogue between neurons and glia, facilitating proper function. Through selectively constitutive and inducible deletion TET1 in the glial lineage in mice, the researchers recapitulate the age-related decline in repair of demyelinated lesions, effectively demonstrating young adult mice with no glial TET1 are incapable of producing functional myelin and behave like old mice.
“This newly identified age-related decline in TET1 may account for the inability of older individuals to form new myelin,” says Casaccia. “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.”
The authors are currently investigating whether increasing TET1 levels in older mice can rejuvenate oligodendroglial cells, rescue myelin formation and restore neuro-glial communication.
