More MS news articles for September
remyelination fail in multiple sclerosis?
Nat Rev Neurosci 2002 Sep;3(9):705-14
Department of Clinical Veterinary Medicine and Cambridge Centre for
Brain Repair, University of Cambridge, Madingley Road, Cambridge CB3 0ES,
Multiple sclerosis is a common cause of neurological disability in young
adults. The disease is complex #151; its aetiology is multifactorial and
largely unknown; its pathology is heterogeneous; and, clinically, it is
difficult to diagnose, manage and treat. However, perhaps its most frustrating
aspect is the inadequacy of the healing response of remyelination. This
regenerative process generally occurs with great efficiency in experimental
models, and sometimes proceeds to completion in multiple sclerosis. But
as the disease progresses, the numbers of lesions in which demyelination
persists increases, significantly contributing to clinical deterioration.
Understanding why remyelination fails is crucial for devising effective
methods by which to enhance it.
Although spontaneous regeneration after central nervous system (CNS) damage
is rare, demyelinated CNS axons can undergo remyelination. Remyelination
can be very efficient, especially in experimental models. However, in multiple
sclerosis (MS) — the most common demyelinating disease of adulthood — remyelination
often fails, contributing to clinical deterioration. Devising means by
which remyelination can be enhanced or reactivated in MS is a major therapeutic
goal that will probably be achieved by understanding how remyelination
works and why it fails.
Remyelination proceeds in two main stages. The first involves the recruitment
of oligodendrocyte progenitor cells (OPCs) by proliferation and possibly
migration. The second involves the OPCs engaging demyelinated axons and
differentiating into myelin-sheath forming oligodendrocytes. Potentially,
remyelination can fail at either of these two stages, both of which become
less efficient as a consequence of ageing (which probably contributes to
the decline in remyelination efficiency during the course of the disease).
Emerging clinical evidence indicates that OPCs might be a target of the
disease process; this would have implications for the generation of sufficient
OPCs for the recruitment phase. Other histopathological evidence indicates
that, in some cases, non-remyelinating lesions are full of OPCs and immature
oligodendrocytes that fail to become remyelinating oligodendrocytes, implying
a failure of differentiation.
What factors govern OPC recruitment and differentiation during remyelination?
Developmental studies of myelination have provided valuable clues to the
factors that might govern remyelination, although there are differences
between the two processes. Nevertheless, developmental studies indicate
that many signalling molecules, including growth factors, cytokines and
chemokines, neurotransmitters and the extracellular matrix (ECM), are likely
to be involved in OPC recruitment; in some instances, supporting evidence
has been provided by experimental models of remyelination.
Regulators of the differentiation of OPCs into oligodendrocytes include
growth factors, ECM, adhesion molecules and the Notch-jagged pathway. Details
of the intracellular signalling mechanisms and transcriptional regulation
of differentiation have emerged and might provide the basis for pharmacological
approaches to manipulating this process. However, the crucial mechanism
by which an oligodendrocyte ensheaths axons with a spiral wrap that finally
compacts to form the myelin sheath is a fundamental aspect of both myelination
and remyelination about which little is known.
A picture is emerging of a complex matrix of signals that is required for
successful remyelination. This matrix involves a diversity of molecules,
fulfilling distinct roles and expressed at critical times during the process.
Paradoxically, the inflammatory process that is associated with demyelination
might also trigger the cascade of events that creates an environment that
It is not clear why remyelination fails in MS, but given the complexity
of the signalling environment, a hypothesis emerges — the 'dysregulation'
hypothesis — in which there is no individual villain of the piece, but
rather a breakdown in the regulation of myelination signalling. The future
challenge will be to identify the non-redundant trigger factors that create
a pro-remyelination environment, and establish whether their manipulation
will form the basis of remyelination-enhancing therapies for MS.
Nature © Macmillan Publishers Ltd 2002