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Glia. 2018 Sep;66(9):1999-2012. doi: 10.1002/glia.23453. Epub 2018 May 15.

Conditional depletion of GSK3b protects oligodendrocytes from apoptosis and lessens demyelination in the acute cuprizone model.

Author information

1
Veterans Administration Pittsburgh, University Drive C Bldg 30, Pittsburgh, Pennsylvania.
2
Department of Cell Biology, Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
Department of Neurology/PIND, University of Pittsburgh, 3501 5th Avenue, Pittsburgh, Pennsylvania.
4
Department of Neurology, University of Kentucky, 800 Rose St, Lexington, Kentucky.

Abstract

Apoptosis is recognized as the main mechanism of oligodendrocyte loss in Multiple Sclerosis caused either by immune mediated injury (Barnett & Prineas, ) or a direct degenerative process (oligodendrogliapathy; Lucchinetti et al., ). Cuprizone induced demyelination is the result of non-immune mediated apoptosis of oligodendrocytes (OL) and represents a model of oligodendrogliapathy (Simmons, Pierson, Lee, & Goverman, ). Glycogen Synthase Kinase (GSK) 3b has been shown to be pro-apoptotic for cells other than OL. Here, we sought to investigate whether GSK3b plays a role in cuprizone-induced apoptosis of OL by using a novel inducible conditional knockout (cKO) of GSK3b in mature OL. While depletion of GSK3b has no effect on survival of uninjured OL, it increases survival of mature OL exposed to cuprizone. We show that GSK3b-deficient OLs are protected against caspase-dependent, but not against caspase-independent apoptosis. Active GSK3b is present in the nuclei of OL at peak of caspase-dependent apoptosis. Significant preservation of myelinated axons is associated with GSK3b depletion and glial cell activation is markedly reduced. Collectively, the data show that GSK3b is pro-apoptotic for caspase-dependent cell death, likely through activation of nuclear GSK3b and its depletion promotes survival of oligodendrocytes and attenuates myelin loss.

KEYWORDS:

GSK3b; cell death; glia; multiple sclerosis

PMID:
29761559
DOI:
10.1002/glia.23453
[Indexed for MEDLINE]

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