Critical Role for PAR1 in Kallikrein 6-Mediated Oligodendrogliopathy

Glia, 2013 · DOI: 10.1002/glia.22534 · Published: September 1, 2013

Simple Explanation

Kallikrein 6 (Klk6) is a protease found in the brain, especially in cells called oligodendroglia. This study found that when Klk6 levels are high, it can damage these cells. The damage happens because Klk6 activates a receptor called PAR1 on the oligodendroglia. When PAR1 is activated, it stops the cells from growing properly and making myelin, which is important for protecting nerve fibers. This suggests that blocking PAR1 could be a way to protect oligodendroglia and help the brain repair itself after injury or in diseases like multiple sclerosis.

Study Duration

Not specified

Participants

Mice deficient in PAR1 (PAR1−/−) or PAR2 (PAR2−/−)

Evidence Level

Not specified

Key Findings

1
Klk6 mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion.
2
Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling.
3
Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR+/+ but not PAR−/− mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1+ oligodendrocytes.

Research Summary

This study demonstrates that Klk6 signals through PAR1 to regulate oligodendrocyte process stability and extension, myelin gene expression and cell survival in the presence of oligotoxic agents. Elevated levels of Klk6 and other PAR1 agonists were also shown to directly mediate white matter degeneration in a PAR1-dependent manner, in vivo. These findings therefore define PAR1-agonists such as Klk6 and thrombin as important mediators of white matter pathology and as potential new targets for the development of therapies to prevent oligodendrocyte injury and to promote myelin regeneration.

Practical Implications

Therapeutic Target

PAR1 and its agonists, such as Klk6, may serve as targets for the development of new oligo-protective approaches.

Prevent Demyelination

Therapeutic targeting of PAR1 may circumvent the oligotoxic properties of PAR1 agonists that can become deregulated at sites of CNS injury.

Promote Remyelination

Future studies will be needed to determine how PAR1 or its agonists may be therapeutically targeted to prevent demyelination and promote remyelination in cases of CNS injury or disease.

Study Limitations

1
The study indicates that PAR2 does not play an essential role in Klk6-mediated oligodendrogliopathy in vitro, but it cannot exclude other regulatory roles.
2
The generalizability of the Erk1/2 signaling findings in an oligodendrocyte cell line to primary oligodendroglia at progenitor and more mature stages of development will need to be determined in future studies.
3
The precise effects of Klk6 in CNS white matter are not fully understood.

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