Targeting Protease-Activated Receptors (PARs) to Promote Myelin Regeneration and Stem Cell Differentiation Across the Life Span
Genetic deletion of PAR1 increases the abundance and thickness of myelin in the adult spinal cord, as cited in Glia, 2015 (Yoon et al.).
High levels of PAR1 signaling promote demyelination while reduced levels promote myelin repair by fostering AKT and ERK signaling. Targeting PAR1 represents a new therapeutic target to promote myelin repair in the developing and adult nervous system.
Recent studies from Dr. Scarisbrick's Neuroregeneration and Neurorehabilitation Laboratory demonstrate that aberrant protease signaling at protease-activated receptor 1 (PAR1) promotes demyelination and actively suppresses the differentiation of oligodendrocyte precursor cells (OPCs) that are the mediators of both myelination and of innate myelin repair (remyelination). Thrombin is a high affinity activator of PAR1 and hence this receptor is often referred to as the thrombin receptor. Other serine proteases relevant to the pathogenesis of demyelinating conditions such as multiple sclerosis also activate PAR1, albeit with lower affinity, including kallikrein 6 (neurosin), plasmin, activated protein C, granzyme A and MMP-1—as cited in Brain, 2002 (Scarisbrick et al.); Current Topics in Microbiology and Immunology, 2008 (Scarisbrick); and Glia, 2015, (Yoon et al.).
Dr. Scarisbrick's research team is testing the hypothesis that excessive protease signaling at PARs promotes demyelination and actively blocks the differentiation of oligodendrocyte progenitor cells and myelin regeneration. Remyelination facilitates the conduction of nerve impulses and information processing. In addition, oligodendrocytes metabolically support axons facilitating function and providing protection from degeneration.
Therapies to foster myelin regeneration therefore are attractive for both relapsing remitting and the more progressive stages of multiple sclerosis as well as many other neurological conditions that involve dysmyelination. New studies, funded by the National Multiple Sclerosis Society, are underway to determine whether the thrombin receptor (PAR1) represents a critical extracellular switch regulating the continuum of central nervous system myelination, demyelination and myelin regeneration.
The long-term goal of these studies is to identify protease-activated receptors as new targets for pharmacotherapy to promote myelin repair in the injured brain and spinal cord.
This research is supported by a published U.S. Patent US2016/0000791 “PAR1 modulation to alter myelination” This research is funded by National Multiple Sclerosis Society RG4958 "Targeting Protease Activated Receptor 1 to Promote Myelin Repair."