Results published in JCI suggest that overexpression of TIP30 disrupts required signaling pathway.



Scientists at Keio University School of Medicine have figured why precursors of oligodendrocytes, which are present in diseased areas of the brains of individuals with multiple sclerosis (MS), do not develop into oligodendrocytes and produce the nerve cell sheath. In MS patients, the protein TIP30 is abnormally overexpressed, preventing a signaling pathway, the Notch1 intracellular domain, from inducing the precursors to turn into oligodendrocytes.


In healthy tissues, high levels of the protein Contactin interact with Notch1 to trigger the development of oligodendrocyte precursors into the oligodendrocytes themselves. In MS, oligodendrocyte precursor cells (OPCs) persist near demyelinated axons but inefficiently differentiate into oligodendrocytes and remyelinate these axons.


The team hypothesized that injured axons fail to present Contactin and thus tracked axoglial Contactin/Notch1 signaling in situ, using immunohistochemistry in brain tissue from MS patients.


On the contrary, the researchers found that Contactin expression was upregulated on demyelinated axons. Further analysis revealed that Notch1-positive OPCs accumulated in Contactin-positive lesions and that the receptor was engaged, as shown by cleavage to Notch1- intracellular domain (NICD).


However nuclear translocalization of NICD, required for myelinogenesis, was virtually absent in the 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 also 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,” the authors write in their paper, which appears in the December 22 edition of the Journal of Clinical Investigation.








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