Revisiting Notch in remyelination of multiple sclerosis lesions.
MS results from destruction of the protective myelin sheath surrounding axons, which prevents the transmission of nerve impulses. Precursors of oligodendrocytes, the cells capable of myelinating axons, are preserved in demyelinating lesions; however, why these precursors do not differentiate into mature oligodendrocytes and remyelinate axons is unknown. Contactin is a noncanonical Notch receptor ligand that mediates oligodendrocyte differentiation. In this issue of the JCI, Nakahara et al. show that Contactin is abundantly expressed on demyelinated axons in human chronic MS lesions and that Notch1 is activated in oligodendrocyte precursor cells (see the related article beginning on page 169). However, Notch1 intracellular domain coassociates with the nuclear transporter Importin beta but fails to show evidence of nuclear translocation. These cytoplasmic aggregates also contain TAT-interacting protein 30 kDa (TIP30), a proapoptotic factor, which inhibits nuclear transport and, consequently, Notch1-mediated oligodendrocyte differentiation and remyelination. These data target TIP30 as a new pathogenic factor in MS.
Brosnan
Celia F
CF
Department of Pathology, Albert Einstein College of Medicine, New York, NY 10461, USA. brosnan@aecom.yu.edu
John
Gareth R
GR
D000123:Acetyltransferases / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism*; D058966:Contactins; D006801:Humans; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D058966:Contactins; D051881:Receptor, Notch1; D014157:Transcription Factors; D000123:Acetyltransferases; C111246:HTATIP2 protein, human