Summary: A global knockout of the thrombin receptor PAR1 accelerates myelin development. The findings could help with the development of treatments for diseases associated with demyelination, like multiple sclerosis.
Source: Mayo Clinic
A molecular switch has the ability to turn on a substance in animals that repairs neurological damage in disorders such as multiple sclerosis (MS), Mayo Clinic researchers discovered. The early research in animal models could advance an already approved Food and Drug Administration therapy and also could lead to new strategies for treating diseases of the central nervous system.
Research by Isobel Scarisbrick, Ph.D., published in the Journal of Neuroscience finds that by genetically switching off a receptor activated by blood proteins, named Protease Activated Receptor 1 (PAR1), the body switches on regeneration of myelin, a fatty substance that coats and protects nerves.
“Myelin regeneration holds tremendous potential to improve function. We showed when we block the PAR1 receptor, neurological healing is much better and happens more quickly. In many cases, the nervous system does have a good capacity for innate repair,” says Dr. Scarisbrick, principal investigator and senior author. “This sets the stage for development of new clinically relevant myelin regeneration strategies.”
Myelin, Thrombin and the Nervous System
Myelin acts like a wire insulator that protects electrical signals sent through the nervous system. Demyelination, or injury to the myelin, slows electrical signals between brain cells, resulting in loss of sensory and motor function. Sometimes the damage is permanent. Demyelination is found in disorders such as MS, Alzheimer’s disease, Huntington’s disease, schizophrenia and spinal cord injury.
Thrombin is a protein in blood that aids in healing. However, too much thrombin triggers the PAR1 receptor found on the surface of cells, and this blocks myelin production. Oligodendrocyte progenitor cells capable of myelin regeneration are often found at sites of myelin injury, including demyelinating injuries in multiple sclerosis.
“These oligodendroglia fail to differentiate into mature myelin regenerating cells for reasons that remain poorly understood,” says Dr. Scarisbrick. “Our research identifies PAR1 as a molecular switch of myelin regeneration. In this study, we demonstrate that blocking the function of the PAR1, also referred to as the thrombin receptor, promotes myelin regeneration in two unique experimental models of demyelinating disease.”
The research focused on two mouse models. One was an acute model of myelin injury and the other studied chronic demyelination, each modeling unique features of myelin loss present in MS, Alzheimer’s disease and other neurological disorders. Researchers genetically blocked PAR1 to block the action of excess thrombin.
The research not only discovered a new molecular switch that turns on myelin regeneration, but also discovered a new interaction between the PAR1 receptor and a very powerful growth system called brain derived neurotropic factor (BDNF). BDNF is like a fertilizer for brain cells that keeps them healthy, functioning and growing.
Significantly, the researchers found that a current Food and Drug Administration-approved drug that inhibits the PAR1 receptor also showed ability to improve myelin production in cells tested in the laboratory.
“It is important to say that we have not and are not advocating that patients take this inhibitor at this time,” says Dr. Scarisbrick. “We have not used the drug in animals yet, and it is not ready to put in patients for the purpose of myelin repair. Using cell culture systems, we are showing that this has the potential to improve myelin regeneration.”
Additional research is needed to verify and advance the findings toward clinical practice.
Funding: The study was made possible by a grant from the National Multiple Sclerosis Society with support from the Mayo Clinic Rehabilitation Medicine Research Center, the Center for Multiple Sclerosis and Autoimmune Neurology and the Mayo Clinic Center for Regenerative Medicine.
Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain
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.
Replacement 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.