April 03, 2018
Glial cells, including astrocytes and oligodendrocytes, play key roles in regulating brain function and its response to injury. Researchers in Mayo Clinic's Neuroregeneration and Neurorehabilitation Laboratory have conducted multiple studies geared toward identifying new regenerative and rehabilitative approaches for disorders of the central nervous system, with particular emphasis on demyelinating conditions and trauma affecting the spinal cord.
Four types of protease activated receptors (PARs) are expressed in the brain and spinal cord and function as key regulators of neural cell behavior. Researchers are only beginning to understand the physiological functions and significance of these unique G protein-coupled receptors. In recent studies, Mayo Clinic researchers have demonstrated that genetic or pharmacologic inhibition of PAR1 activation could effectively reduce its dysmyelinating effects. These findings led researchers to hypothesize that PAR2 also may play a significant role in myelination, particularly since it is preferentially activated by a number of proteases enriched in the CNS, including kallikrein 6 (also referred to as neurosin). Kallikrein 6 belongs to a family of enzymes that can degrade myelin and signal oligodendrocytes to stop making myelin.
In a study published in Glia in 2017, Mayo researchers examined the role of PAR2 in myelin development and repair, in genetically deficient PAR2-/- mice and in cell culture. Mayo researchers reported that PAR2-/- mice produce more myelin throughout the life span than PAR2+/+ mice. They also have improved myelin resiliency after traumatic spinal cord injury and an accelerated pattern of myelin regeneration after focal demyelination.
"Our results demonstrate that genetic deletion of PAR2 accelerates myelin production. At birth, this acceleration is accompanied by higher proteolipid protein levels (PLPs), the building blocks of myelin, in the spinal cord. During adulthood, PAR2-/- mice exhibited higher levels of myelin basic protein and thickened myelin sheaths," explains Isobel A. Scarisbrick, Ph.D., director of the Neuroregeneration and Neurorehabilitation Laboratory at Mayo Clinic's campus in Minnesota and the study's principal investigator. "Genetic targeting of PAR2 fostered myelin regeneration in the adult spinal cord and was associated with myelin preservation after traumatic spinal cord injury."
Myelinating cells insulate axons to facilitate the conduction of nerve impulses and provide axons with metabolic and trophic support. Thus, preserving and restoring myelin can have a considerable beneficial effect on neurological recovery after spinal cord injury and in other neurological conditions such as multiple sclerosis.
Mayo researchers also found that in addition to enhancements in spinal cord myelin, PAR2 loss of function was also associated with:
- Increased numbers of Olig2- and CC1-positive oligodendrocytes
- Increased levels of cyclic adenosine monophosphate (cAMP) and extracellular signal-related kinase 1/2 (ERK1/2) signaling
In the same study, Mayo researchers observed that over-activation of PAR2 impeded myelin production. These effects included:
- Reduced expression of PLP, an effect that was reversed or mitigated by brain-derived neurotrophic factor (BDNF) treatment, a promyelinating growth factor that signals through cAMP
- These findings suggest that PAR2 is a significant regulator of neurotrophic factor signaling and can be targeted to unleash the pro-regenerative capacity of growth factors such as BDNF.
"Overall, these are the first studies to identify PAR2 as a key suppressor of myelination, both in the developing and adult spinal cord, and to identify this unique receptor as a potential new drug target to promote myelin protection and repair," says Dr. Scarisbrick.
These studies were supported by the Mayo Clinic Rehabilitation Medicine Research Center, the Mayo Clinic Center for Regenerative Biotherapeutics, the NIH R01NS052741-10 grant and the National Multiple Sclerosis Society RG4958 grant.
For more information
Yoon H, et al. Protease activated receptor 2 controls myelin development, resiliency and repair. Glia. 2017;65:2070.