Our findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system.

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

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.

Multiple sclerosis is an autoimmune disease of the CNS resulting in degeneration of myelin sheaths and loss of oligodendrocytes, which means that protection and electrical insulation of axons and rapid signal propagation are impaired, leading to axonal damage and permanent disabilities. Partial replacement of lost oligodendrocytes and remyelination can occur as a result of activation and recruitment of resident oligodendroglial precursor cells. However, the overall remyelination capacity remains inefficient because precursor cells often fail to generate new oligodendrocytes. Increasing evidence points to the existence of several molecular inhibitors that act on these cells and interfere with their cellular maturation. The p57kip2 gene encodes one such potent inhibitor of oligodendroglial differentiation and this study sheds light on the underlying mode of action. We found that subcellular distribution of the p57kip2 protein changed during differentiation of rat, mouse, and human oligodendroglial cells both in vivo and in vitro. Nuclear export of p57kip2 was correlated with promoted myelin expression, higher morphological phenotypes, and enhanced myelination in vitro. In contrast, nuclear accumulation of p57kip2 resulted in blocked oligodendroglial differentiation. Experimental evidence suggests that the inhibitory role of p57kip2 depends on specific interactions with binding proteins such as LIMK-1, CDK2, Mash1, and Hes5 either by controlling their site of action or their activity. Because functional restoration in demyelinating diseases critically depends on the successful generation of oligodendroglial cells, a therapeutic need that is currently unmet, the regulatory mechanism described here might be of particular interest for identifying suitable drug targets and devising novel therapeutic approaches.

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Our findings suggest that a specific activation of the CXCR7 receptor could provide a means to promote oligodendroglial differentiation in the diseased or injured central nervous system.

The mechanisms preventing efficient remyelination in the adult mammalian central nervous system after demyelinating inflammatory diseases, such as multiple sclerosis, are largely unknown. Partial remyelination occurs in early disease stages, but repair capacity diminishes over time and with disease progression. We describe a potent candidate for the negative regulation of oligodendroglial differentiation that may underlie failure to remyelinate. The p57kip2 gene is dynamically regulated in the spinal cord during MOG-induced experimental autoimmune encephalomyelitis. Transient down-regulation indicated that it is a negative regulator of post-mitotic oligodendroglial differentiation. We then applied short hairpin RNA-mediated gene suppression to cultured oligodendroglial precursor cells and demonstrated that downregulation of p57kip2 accelerates morphological maturation and promotes myelin expression. We also provide evidence that p57kip2 interacts with LIMK-1, implying that p57kip2 affects cytoskeletal dynamics during oligodendroglial maturation. These data suggest that sustained down-regulation of p57kip2 is important for oligodendroglial maturation and open perspectives for future therapeutic approaches to overcome the endogenous remyelination blockade in multiple sclerosis.differentiation ͉ intrinsic inhibitor ͉ multiple sclerosis ͉ oligodendrocyte ͉ remyelination

The p57kip2 gene encodes a member of the cyclin-dependent kinase inhibitor family, proteins known to block G 1/S transition during the mammalian cell cycle. We observed that expression of p57kip2 in Schwann cells of the developing and injured adult peripheral nervous system is dynamically regulated. Using gene knockdown by means of vector-based RNA interference in cultured primary Schwann cells we found that reduced levels of p57kip2 lead to cell cycle exit, actin filament stabilization, altered cell morphology and growth, and down-regulation of promyelinating markers as well as induction of myelin genes and proteins. In addition, we could demonstrate that in vitro myelination is enhanced by p57kip2-suppressed Schwann cells. Using microarray technology we found that these cellular reactions are specific to lowered p57kip2 expression levels and detected a shift of the transcriptional expression program toward the pattern known from Schwann cells in developing peripheral nerves. Because in the absence of axons primary Schwann cells normally do not display differentiation-associated reactions, we conclude that we have identified a mechanism and an important intrinsic negative regulator of myelinating glia differentiation.glia ͉ immune neuropathies ͉ myelin ͉ peripheral nerve A xons are tightly associated with myelinating glial cells in the vertebrate nervous system, Schwann cells in the peripheral nervous system, and oligodendrocytes in the CNS. These cells wrap around axons in a radial growth and migration process and establish multiple lipid-and protein-rich layers to support and electrically insulate them, thus enabling saltatory propagation of electrical signals. As a result of axonal segregation, myelinating Schwann cells are associated with large-caliber axons in a 1:1 relationship and represent highly specialized and differentiated cells. Schwann cells derive from neural crest, and their differentiation during peripheral nerve development was shown to depend on a variety of genes, such as integrins, the transcription factors Sox10, Oct-6, and Krox20, or neuregulin-, p75-LNGFR, and Lgi4 signaling cascades (1-7).Cell cycle exit is a prerequisite for myelinating glial cell differentiation followed by morphological changes as well as the expression and deposition of myelin proteins within the layers of lipid sheaths. The establishment of such a complex morphology depends on regulated cytoskeletal dynamics, e.g., actin filament turnover. This was demonstrated by means of application of cytochalasin D, a mycotoxin that interferes with actin filament assembly. Differentiation and myelination of Schwann cells cocultured with dorsal root ganglion (DRG) neurons were found to be blocked when this drug was added to the culture medium, indicating that actin filament dynamics is imperative for Schwann cell growth and morphological adaptation during the myelination process (8). Nevertheless, the question as to whether naturally occurring regulators of cytoskeletal dynamics, acting during nerve development and/or after inju...