Factors that retard remyelination in multiple sclerosis with a focus on TIP30: a novel therapeutic target

Abstract

In the CNS oligodendrocytes produce myelin and ensheath individual axons after birth. Demyelination disables saltatory conduction and leads to loss of neural functions. Oligodendrocyte precursor cells (OPCs) are immature and abundant reservoir cells in the adult brain that are capable of differentiating into myelinating oligodendrocytes. Upon demyelination insults, OPCs are spontaneously induced to differentiate in order to remyelinate denuded axons and promote functional recovery. While remyelination is an efficient regenerative process in the CNS, it often fails in the chronic phase of multiple sclerosis (MS). OPCs are nonetheless preserved in many MS lesions, suggesting that arrested OPC differentiation underlies remyelination failure in chronic MS. Understanding the molecular pathology of this arrested differentiation and remyelination failure in chronic MS is critical for developing remyelination medicines that will promote a full functional recovery in these patients. Recently, TIP30 was identified as an inhibitor of OPC differentiation in MS. TIP30 inhibits proper nucleocytoplasmic transport and thus disables nuclear import of transcription factors that are required for differentiation. TIP30 may also increase susceptibility of OPCs to cell death. In this review, we examine the pathophysiological nature of remyelination failure in chronic MS and discuss the role of TIP30 as a novel therapeutic target.

High-Content Phenotypic Screening and Triaging Strategy to Identify Small Molecules Driving Oligodendrocyte Progenitor Cell Differentiation

“…Compounds identified through this effort have the potential to stimulate endogenous OPCs to differentiate and remyelinate demyelinated axons, thereby contributing new modalities of treatment for neurodegenerative diseases such as MS. A small-molecule approach to achieve this objective has a higher chance of resulting in an orally bioavailable therapy that is able to cross the blood-brain barrier and reach the CNS, compared to biological agents. Although significant data exist regarding the pathways and gene expression modifications during OPC differentiation, 5,[15][16][17][18][19] in the context of developing therapeutics there are important considerations concerning the specificity of putative targets. Therefore, we chose the approach of a phenotypic assay to identify compounds competent to initiate differentiation of both rat CG-4 cells and primary OPCs but not of the MSC-derived rodent progenitor cell (C2C12) in a comparable assay format (similar time and stimulus).…”

“…These, in turn, undergo a process of differentiation to become mature oligodendrocytes as evidenced by sequential expression of various biomarkers, including O4 and myelin basic protein (MBP). [1][2][3][4][5][6] Maturing oligodendrocytes are postmitotic cells, characterized morphologically by the extension of numerous and often branched membrane processes. In vivo, processes from a single mature oligodendrocyte wrap and subsequently form compact myelin around up to 50 proximal axons, becoming a segment of their insulating myelin sheath.…”

“…In vivo, processes from a single mature oligodendrocyte wrap and subsequently form compact myelin around up to 50 proximal axons, becoming a segment of their insulating myelin sheath. [2][3][4][5] Multiple Sclerosis (MS) is the most common demyelinating disease of the CNS as well as one of the primary causes of neurological disability in young adults, and loss of oligodendrocytes at MS lesions has long been thought to be a primary contributor to disease. More recently, it has been found that oligodendrocytes are heterogeneous in nature 7 and that a significant number of OPCs migrate to and are present in MS lesions even in the chronic phases.…”

Autoimmune Versus Oligodendrogliopathy: The Pathogenesis of Multiple Sclerosis

“…nuclear transport of transcription factors required for differentiation) within the preserved OPCs in MS lesions (Nakahara et al 2009b). TIP30 is also well known as a pro-apoptotic protein (reviewed in Nakahara et al 2009a), and we indeed observed massive apoptosis when TIP30 was overexpressed in OPCs in vitro (Nakahara et al 2009b). Although possible TIP30 expression in the very early MS lesion remains to be analyzed, the observation in chronic MS lesions suggests by analogy that oligodendrocytes or OPCs may have intrinsic functional defects that lead to demyelination.…”

“…Unlike neurons, oligodendrocytes are highly capable of regeneration and remyelination is a very effective process in the CNS, as observed clinically in patients with ADEM or in experimentally demyelinated animals. However, remyelination is a rather inconsistent process in MS, making remyelination failure one of the key characteristics observed in chronic MS cases (reviewed in Nakahara et al 2009a). Remyelination failure in MS is not due to lack of appropriate cells to be recruited for remyelination, as numerous OPCs, immature cells capable of differentiating into myelinating oligodendrocytes, are observable in many chronic MS lesions (Chang et al 2000;Nakahara and Aiso 2006;Scolding et al 1998;Wolswijk 1998).…”