The complex world of oligodendroglial differentiation inhibitors

Abstract

Myelination is a central nervous system (CNS) process wherein oligodendrocyte-axon interactions lead to the establishment of myelin sheaths that stabilize, protect, and electrically insulate axons. In inflammatory demyelinating diseases such as multiple sclerosis (MS), the degeneration and eventual loss of functional myelin sheaths slows and blocks saltatory conduction in axons, which results in clinical impairment. However, remyelination can occur, and lesions can be partially repaired, resulting in clinical remission. The recruitment and activation of resident oligodendrocyte precursor cells (OPCs) play a critical role in the repair process because these cells have the capacity to differentiate into functional myelinating cells. Mature oligodendrocytes, however, are thought to have lost the capacity to develop new myelin sheaths and frequently undergo programmed cell death in MS. The endogenous capacity to generate new oligodendrocytes in MS is limited, and this is predominantly due to the presence of inhibitory components that block OPC differentiation and maturation. Here, we present an overview of recently identified negative regulators of oligodendroglial differentiation and their potential relevance for CNS repair in MS. Because currently available immunomodulatory drugs for MS mainly target inflammatory cascades outside the brain and fail to repair existing lesions, achieving more efficient lesion repair constitutes an important goal for future MS therapies.

Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions

“…Despite this potential, remyelination fails partially or completely in many MS lesions. Reasons for remyelination failure may include impaired oligodendrocyte precursor differentiation and maturation (3), axo-glial interaction (4), energy homeostasis, and clearance of cytotoxic inflammation (5)(6)(7)(8). Among chronically demyelinated lesions, the pathologically described chronic active and slowly expanding (or "smoldering") lesions (9) might be considered the worst-case scenario of remyelination failure (10), with persistent inflammatory infiltration (macrophages/microglia) and evidence of ongoing demyelination at the lesion edge (11).…”

p57kip2 regulates glial fate decision in adult neural stem cells

“…Functional cell replacement is a consequence of oligodendrocyte precursor cell (OPC) or NSC activation and differentiation (Chang et al, 2000;Picard-Riera et al, 2002;Menn et al, 2006;Nait-Oumesmar et al, 2007;Rivera et al, 2010). Despite its spontaneous character, the overall remyelination efficiency remains low and is further decreased with disease progression, which is thought to be due to the presence of inhibitory factors (Scolding et al, 1998;Wolswijk, 1998;Chang et al, 2000;Chang et al, 2002;Kuhlmann et al, 2008;Kremer et al, 2009;Kremer et al, 2011). Identification of such inhibitory components and knowledge about signal transduction pathways to interfere with thus allow development of strategies to promote cell replacement and endogenous remyelination.…”

NF-κB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications

“…4,5 The process of myelination accelerates during infancy and will be pursued until adolescence. Brain myelin formation during development is initiated by, as yet, poorly identified signals from axons to oligodendrocytes.…”