The Thrombin Receptor is a Critical Extracellular Switch Controlling Myelination

Glia, 2015 · DOI: 10.1002/glia.22788 · Published: May 1, 2015

Simple Explanation

This study investigates the role of the thrombin receptor (PAR1) in myelination, the process of forming a protective sheath around nerve fibers, using genetically modified mice. The researchers found that deleting the PAR1 gene in mice led to earlier and more extensive myelination in the spinal cord, suggesting PAR1 normally acts to suppress this process. The study also found that inhibiting PAR1 with a drug promoted myelin production in cell cultures, indicating PAR1 could be a therapeutic target for improving myelination in conditions like white matter injury.

Study Duration

Not specified

Participants

PAR1+/+ littermates served as controls.

Evidence Level

Not specified

Key Findings

1
PAR1 gene deletion resulted in earlier onset of spinal cord myelination and higher levels of proteolipid protein (PLP) at birth.
2
Adult PAR1−/− mice had higher amounts of myelin basic protein and thicker myelin sheaths.
3
The enhancements in myelination were associated with increases in extracellular-signal-regulated kinase 1/2 and AKT signaling.

Research Summary

Here we show that the thrombin receptor is an essential intrinsic suppressor of spinal cord myelination. Deletion of the gene encoding the thrombin receptor resulted in spinal cord hypermyelination, including more myelinated axons and higher PLP levels at term and the attainment of higher MBP levels, thicker myelin sheaths and enhanced motor activity in adults. The enhancements in myelination observed as a result of PAR1 loss-of-function in vivo were associated with elevations in the activated forms of the pro-myelination signaling intermediates ERK1/2 and AKT.

Practical Implications

Therapeutic target for myelin pathologies

The thrombin receptor could be targeted in myelin pathologies to improve myelin health.

Potential treatment for preterm birth complications

Excessive engagement of the thrombin receptor due to intraventricular or intraparenchymal hemorrhage in preterm birth may lead to a functional blockade of normal myelination.

Enhancement of ERK1/2 and AKT signaling

Absence of PAR1 during myelination, or remyelination, would enhance ERK1/2 and AKT signaling leading to improvements in myelin production.

Study Limitations

1
The link between PAR1 deletion and elevated ERK1/2 and AKT activity is not proven to be a direct cause-and-effect relationship.
2
The impact of global PAR1 deletion on other cell types like astrocytes, microglia, and endothelial cells needs further investigation.
3
Other neuronal and non-neuronal effects that could impact the production of myelin cannot be excluded.

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