Abstract
A prominent feature of demyelinating diseases such as multiple sclerosis (MS) is the degeneration and loss of previously established functional myelin sheaths, which results in impaired signal propagation and axonal damage. However, at least in early disease stages, partial replacement of lost oligodendrocytes and thus remyelination occur as a result of resident oligodendroglial precursor cell (OPC) activation. These cells represent a widespread cell population within the adult central nervous system (CNS) that can differentiate into functional myelinating glial cells to restore axonal functions. Nevertheless, the spontaneous remyelination capacity in the adult CNS is inefficient because OPCs often fail to generate new oligodendrocytes due to the lack of stimulatory cues and the presence of inhibitory factors. Recent studies have provided evidence that regulated intracellular protein shuttling is functionally involved in oligodendroglial differentiation and remyelination activities. In this review we shed light on the role of the subcellular localization of differentiation-associated factors within oligodendroglial cells and show that regulation of intracellular localization of regulatory factors represents a crucial process to modulate oligodendroglial maturation and myelin repair in the CNS.
Highlights
The central nervous system (CNS) is composed of two major classes of cells—neurons and glial cells—the latter of which can be subdivided into astrocytes, microglia and oligodendrocytes.While neurons provide the basis for signal transduction and information processing, glial cells account for a wide range of specific functions
We demonstrated that the cyclin-dependent inhibitor p57kip2 negatively affects myelinating glial cell differentiation in the peripheral and central nervous system and that it controls glial fate decision by adult neural stem cells [55,83,84,85]
EAE was able to recapitulate defective remyelination in vivo [150,151,152]. This is in accordance with the recent finding of Ye and colleagues demonstrating that oligodendroglial differentiation requires transcriptional co-repressors HDAC1 and HDAC2
Summary
The central nervous system (CNS) is composed of two major classes of cells—neurons and glial cells—the latter of which can be subdivided into astrocytes, microglia and oligodendrocytes. Importins compose a family of 16 members, including α and β transportin, that are responsible for transport from the cytoplasm to the nucleus, whereas exportins comprise six family members, including Crm1/XPO/exportin, which is involved in nuclear export [34,35,36] These transport receptors mediate both translocation processes by recognizing specific nuclear localization and export signals (NLSs and NESs, respectively) and directing the distribution of cargo proteins [37,38]. Cu/Zn-superoxide dismutase (G93A) transgenic mice, an animal model for ALS, or in hippocampal neurons in Alzheimer’s disease, revealing cytoplasmic accumulation of the nuclear transport factor 2 [42,44] In demyelinating diseases such as MS, in the context of previously discussed endogenous repair activities, cells of the glial lineage are of primary interest.
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