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J Neurosci. 2020 Jan 7. pii: 2029-19. doi: 10.1523/JNEUROSCI.2029-19.2019. [Epub ahead of print]

Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain.

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Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center.
Department of Physiology and Biomedical Engineering , and Neuroscience Program, Mayo Clinic School of Biomedical Sciences Rochester , MN 55905.
Department of Physical Medicine and Rehabilitation, Rehabilitation Medicine Research Center


Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knockout 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 knockout in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knockout mice occurred in tandem with a skewing of reactive astrocyte signatures towards a pro-repair phenotype. In cell culture, the pro-myelinating 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 pro-myelinating 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.SIGNIFICANCE STATEMENTReplacement of oligodendroglia and myelin regeneration holds tremendous potential to improve function across neurological conditions. Here we demonstrate Protease Activated Receptor 1 (PAR1) is an important regulator of the capacity for myelin regeneration across two experimental murine models of myelin injury. PAR1 is a G-protein coupled receptor densely expressed in the CNS, however there is limited information regarding its physiological roles in health and disease. Using a combination of PAR1 knockout mice, oligodendrocyte monocultures and oligodendrocyte-astrocyte co-cultures, we demonstrate blocking PAR1 improves myelin production by a mechanism related to effects across glial compartments and linked in part to regulatory actions towards growth factors such as BDNF. These findings set the stage for development of new clinically relevant myelin regeneration strategies.

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