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

Glia
Bin XingFranca Cambi

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 thro...Continue Reading

References

Jan 29, 1998·The New England Journal of Medicine·B D TrappL Bö
Sep 20, 2000·Proceedings of the National Academy of Sciences of the United States of America·R V BhatC M Lee
Aug 10, 2001·The Journal of Biological Chemistry·G N Bijur, R S Jope
Jul 31, 2002·The Journal of Cell Biology·Sean P CreganRuth S Slack
Dec 14, 2002·Genesis : the Journal of Genetics and Development·Nathalie H DoerflingerBrian Popko
Mar 5, 2003·Journal of Cell Science·Bradley W Doble, James R Woodgett
Oct 3, 2003·The Journal of Biological Chemistry·Piyajit WatcharasitRichard S Jope
Mar 30, 2004·Annals of Neurology·Michael H Barnett, John W Prineas
Feb 11, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Eric C C CheungRuth S Slack
Jun 14, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jiadong LiPatrizia Casaccia-Bonnefil
Jun 21, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Patrizia De SarnoRichard S Jope
Aug 13, 2008·Molecular and Cellular Biology·Satish PatelJames R Woodgett
Nov 11, 2008·Journal of Neuroscience Methods·Fatemah ChehrehasaAlan Mackay-Sim
Jun 6, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Fuzheng GuoDavid Pleasure
Sep 19, 2009·Acta Neuropathologica·Markus KippCordian Beyer
Oct 27, 2009·Neurobiology of Disease·Amke HesseTanja Kuhlmann
Dec 26, 2009·Annals of Neurology·Andrew P D HendersonJohn W Prineas
Feb 17, 2010·Brain : a Journal of Neurology·Sara VetoZsolt Illes
May 13, 2010·Nature Reviews. Molecular Cell Biology·Helen McNeill, James R Woodgett
Mar 26, 2011·IUBMB Life·Laure DelavalléeSantos A Susin
Jul 26, 2012·Annals of Neurology·John W Prineas, John D E Parratt
Oct 3, 2012·Nature Reviews. Neurology·Robin J M FranklinKenneth J Smith
Feb 9, 2013·Neurotoxicity Research·Karelle BénardaisMartin Stangel
Mar 12, 2013·Neuron·Kaylene M YoungWilliam D Richardson
Apr 23, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Eléonore BeurelRichard S Jope
May 28, 2013·Trends in Immunology·Sarah B SimmonsJoan M Goverman
Mar 25, 2014·Frontiers in Cellular Neuroscience·Viktoria GudiMartin Stangel
Jun 4, 2014·Journal of Neuroinflammation·Jonathan D CherryM Kerry O'Banion
Dec 3, 2014·Neuroscience and Biobehavioral Reviews·Jelle PraetPeter Ponsaerts
Mar 1, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tim ClarnerMarkus Kipp
Aug 28, 2015·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Harshvardhan RolyanQuasar S Padiath

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.