Myelin,
made by oligodendrocytes enwrapping axons with lipid-rich membranes, is
essential for proper central nervous system (CNS) function. Loss of
oligodendrocytes and myelin, known as demyelination, induces severe delay and
failure of action potential propagation, leaves neurons and their axons
vulnerable to degeneration, and causes motor, sensory, and cognitive impairment.
Demyelination
is typically followed by a period of heightened new myelin formation known as
remyelination, which can restore action potential propagation and prevent
neurodegeneration. Remyelination is carried out primarily by newly formed
oligodendrocytes.
However,
the endogenous remyelination response is often incomplete, resulting in chronic
demyelination and limited functional recovery.
Myelin
loss, including in visual gray matter, is a common feature of several
neurodegenerative diseases and injury conditions, and is present in normal
aging. In addition, myelin is malformed or present in insufficient levels in
several neurodevelopmental and neuropsychiatric disorders. By promoting the formation
of new oligodendrocytes and myelin, remyelination therapies may be clinically
important for numerous neurological conditions.
Researchers
have shown that endogenous remyelination is driven by recent oligodendrocyte
loss and is highly efficacious following mild demyelination, but fails to
restore the oligodendrocyte population when high rates of oligodendrocyte loss
occur quickly.
Treatment
with a high dose of LL-341070 substantially increased regenerative
oligodendrogenesis during remyelination. Thus, incomplete remyelination via
therapeutically enhanced oligodendrogenesis is sufficient to recover visual
cortical function.
The
authors concluded that oligodendrocyte gain rate during remyelination is driven
by recent oligodendrocyte loss, rather than a drive to reestablish
oligodendrocyte numbers, indicating that acute signaling around the time of the
loss of myelinating oligodendrocytes induces new oligodendrocyte formation. However,
the exact source of the signal is unknown, and it is unclear if it involves
direct signaling from damaged oligodendrocytes or is mediated by other cell
types.
REFERENCE:
Della-Flora
Nunes, G., Osso, L.A., Haynes, J.A. et al. Incomplete
remyelination via therapeutically enhanced oligodendrogenesis
is sufficient to recover visual cortical function. Nat Commun 16,
732 (2025). https://doi.org/10.1038/s41467-025-56092-6.
