Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy

Joshua E. Burda, Maja Radulovic, Hyesook Yoon, Isobel A Scarisbrick

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Kallikrein 6 (KLK6) is a secreted serine protease preferentially expressed by oligodendroglia in CNS white matter. Elevated levels of KLK6 occur in actively demyelinating multiple sclerosis (MS) lesions and in cases of spinal cord injury (SCI), stroke, and glioblastoma. Taken with recent evidence establishing KLK6 as a CNS-endogenous activator of protease-activated receptors (PARs), we hypothesized that KLK6 activates a subset of PARs to regulate oligodendrocyte physiology and potentially pathophysiology. Here, primary oligodendrocyte cultures derived from wild type or PAR1-deficient mice and the murine oligodendrocyte cell line, Oli-neu, were used to demonstrate that Klk6 (rodent form) mediates loss of oligodendrocyte processes and impedes morphological differentiation of oligodendrocyte progenitor cells (OPCs) in a PAR1-dependent fashion. Comparable gliopathy was also elicited by the canonical PAR1 agonist, thrombin, as well as PAR1-activating peptides (PAR1-APs). Klk6 also exacerbated ATP-mediated oligodendrogliopathy in vitro, pointing to a potential role in augmenting excitotoxicity. In addition, Klk6 suppressed the expression of proteolipid protein (PLP) RNA in cultured oligodendrocytes by a mechanism involving PAR1-mediated Erk1/2 signaling. Microinjection of PAR1 agonists, including Klk6 or PAR1-APs, into the dorsal column white matter of PAR1+/+ but not PAR1-/- mice promoted vacuolating myelopathy and a loss of immunoreactivity for myelin basic protein (MBP) and CC-1+ oligodendrocytes. These results demonstrate a functional role for Klk6-PAR1 signaling in oligodendroglial pathophysiology and suggest that antagonists of PAR1 or its protease agonists may represent new modalities to moderate demyelination and to promote myelin regeneration in cases of CNS white matter injury or disease.

Original languageEnglish (US)
Pages (from-to)1456-1470
Number of pages15
JournalGLIA
Volume61
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Kallikreins
Oligodendroglia
Proteinase-Activated Receptors
Proteolipids
Peptides
Myelin Basic Protein
Spinal Cord Diseases
Microinjections
Serine Proteases
Demyelinating Diseases
Glioblastoma
Myelin Sheath
Spinal Cord Injuries
Thrombin
Multiple Sclerosis
Regeneration
Rodentia
Peptide Hydrolases
Stem Cells
Adenosine Triphosphate

Keywords

  • Demyelination
  • Myelin
  • Oligodendrocyte
  • Protease-activated receptor
  • Spinal cord
  • Thrombin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. / Burda, Joshua E.; Radulovic, Maja; Yoon, Hyesook; Scarisbrick, Isobel A.

In: GLIA, Vol. 61, No. 9, 09.2013, p. 1456-1470.

Research output: Contribution to journalArticle

Burda, Joshua E. ; Radulovic, Maja ; Yoon, Hyesook ; Scarisbrick, Isobel A. / Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy. In: GLIA. 2013 ; Vol. 61, No. 9. pp. 1456-1470.
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