Identification of a factor inhibiting nucleocytoplasmic transport and differentiation within preserved oligodendrocyte precursor cells in multiple sclerosis: a possible cause for remyelination failure

• Published in: Multiple sclerosis 2008-09, Vol.14, p.S8-S8
• Main Authors: Nakahara, J, Kanekura, K, Nawa, M, Aiso, S, Suzuki, N
• Format: Article
• Language: English
• ISSN: 1352-4585

Background: Adult CNS retains its ability to spontaneously repair myelin after demyelinating insults. In MS, however, such remyelination is rather inconsistent and often fails, leading to sustained neurological deficits in patients. Oligodendrocyte precursor cells (OPCs) persist near the demyelinated axons arising in MS, but inefficiently differentiate into oligodendrocytes and remyelinate them, of which pathogenesis remains elusive. A recent study revealed that axonal Contactin acts as a positive Iigand for oligodendroglial Notchl receptor to induce differentiation and myelination. Expression of Contactin on axonal surfaces is dependent upon neuronal electrical activity whereas axonal damage is observed in MS lesions. Objective: We have initially hypothesized that injured axons in MS fail to present Contactin, which may contribute to remyelination failure. Methods: Axoglial Contactin-Notch1 signaling was tracked in situ using 10 autopsied MS brain materials containing chronic demyelinated lesions. Results: Instead, we found that Contactin is saturated on many demyelinated axons, Notch1-positive OPCs accumulate in Contactin-positive lesions, and the receptor is engaged as shown by cleavage to Notch1-intracellular domain (NICD), indicating that the initiation of axoglial signaling is not altered in MS. However, nuclear translocalization of NICD, required for myelinogenesis, is substantially reduced in these OPCs. NICD and related proteins carrying nuclear localization signals are associated with the nuclear transporter Importin beta , but are nonetheless trapped in their cytoplasm. We have identified an ectopic expression of TIP30, a direct inhibitor of Importin beta , co-localized with cytoplasmic NICD-Importin beta complex in these OPCs. Over-expression of TIP30 in OPC cell lines in vitro resulted in cytoplasmic entrapment of NICD and arrest of differentiation upon stimulation with Contactin-Fc. Conclusions: Our observations suggest that an intrinsic nucleocytoplasmic transport blockade by TIP30 within OPCs may be involved in the pathogenesis of remyelination failure in MS.