Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis
Jin Nakahara, Kohsuke Kanekura, Mikiro Nawa, Sadakazu Aiso, Norihiro Suzuki
Jin Nakahara, Kohsuke Kanekura, Mikiro Nawa, Sadakazu Aiso, Norihiro Suzuki
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Research Article

Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis

Abstract

Oligodendrocyte precursor cells (OPCs) persist near the demyelinated axons arising in MS but inefficiently differentiate into oligodendrocytes and remyelinate these axons. The pathogenesis of differentiation failure remains elusive. We initially hypothesized that injured axons fail to present Contactin, a positive ligand for the oligodendroglial Notch1 receptor to induce myelination, and thus tracked axoglial Contactin/Notch1 signaling in situ, using immunohistochemistry in brain tissue from MS patients containing chronic demyelinated lesions. Instead, we found that Contactin was saturated on demyelinated axons, Notch1-positive OPCs accumulated in Contactin-positive lesions, and the receptor was engaged, as demonstrated by cleavage to Notch1-intracellular domain (NICD). However, nuclear translocalization of NICD, required for myelinogenesis, was virtually absent in these cells. NICD and related proteins carrying nuclear localization signals were associated with the nuclear transporter Importin but were trapped in the cytoplasm. Abnormal expression of TIP30, a direct inhibitor of Importin, was observed in these OPCs. Overexpression of TIP30 in a rat OPC cell line resulted in cytoplasmic entrapment of NICD and arrest of differentiation upon stimulation with Contactin-Fc. Our results suggest that extracellular inhibitory factors as well as an intrinsic nucleocytoplasmic transport blockade within OPCs may be involved in the pathogenesis of remyelination failure in MS.

Authors

Jin Nakahara, Kohsuke Kanekura, Mikiro Nawa, Sadakazu Aiso, Norihiro Suzuki

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Figure 4

Abnormal expression of Lamin B1 and TIP30 in OPCs in MS lesions.

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Abnormal expression of Lamin B1 and TIP30 in OPCs in MS lesions. (A) The...
(A) The expression of Lamin B1 is virtually undetectable in normal cerebral white matter from a control subject. (B) The expression is increased in a MS demyelinated lesion (surrounded by broken line) compared with nearby normal-appearing white matter. (C–E; higher magnification) Overexpressed Lamin B1 colocalizes with cytoplasmic NICD aggregates in the OPCs (note that the most of these cytoplasmic NICD–aggregated cells are positive for Olig1, an OPC marker [ref. 24], as shown in Figure 2), but not with nuclear envelopes. (F) TIP30 is undetectable except in small vessels in normal cerebral white matter from a control subject. (G) TIP30 expression is markedly increased in a MS demyelinated lesion (demyelinated area and normal-appearing white matter demarcated by broken line). (H–J) Overexpressed TIP30, an inhibitor of Importin β (19), is associated with Importin β in the OPCs (arrows). (K–M; higher magnification) In a few cells with relatively lower expression of TIP30 (e.g., the lower cell in the pictures), Importin β that is not colocalized with TIP30 (arrows) gathers near the nuclear envelope (arrowheads); some appears to have entered the nucleus. Scale bars: 250 μm (A, B, F, and G); 10 μm (C–E and K–M); 25 μm (H–J).