Journal
JOURNAL OF NEUROSCIENCE
Volume 40, Issue 7, Pages 1483-1500Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2029-19.2019
Keywords
astrocyte; brain derived neurotrophic factor; myelin; oligodendrocyte progenitor cells; protease activated receptor; regeneration
Categories
Funding
- National Institutes of Health [R01NS052741-10, R21NS107946, G-1510-06548]
- National Multiple Sclerosis Society [G-1508-05951, RG-190133209]
- Mayo Clinic Centerfor Regenerative Medicine
- Eugene and Marcia Applebaum Fellowship from the Center for MS and Autoimmune Neurology
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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.
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