Blocking the thrombin receptor promotes repair of demyelinated lesions in the adult brain

Hyesook Yoon, Chan Il Choi, Erin M. Triplet, Monica R. Langley, Laurel S. Kleppe, Ha Neui Kim, Whitney L. Simon, Isobel A. Scarisbrick

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knock-out of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knock-out in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knock-out mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.

Original languageEnglish (US)
Pages (from-to)1483-1500
Number of pages18
JournalJournal of Neuroscience
Volume40
Issue number7
DOIs
StatePublished - Feb 12 2020

Keywords

  • Astrocyte
  • Brain derived neurotrophic factor
  • Myelin
  • Oligodendrocyte progenitor cells
  • Protease activated receptor
  • Regeneration

ASJC Scopus subject areas

  • Neuroscience(all)

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