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The role of endoplasmic reticulum quality control system in the biology of the major myelin glycoproteins Open Access


Other title
Endoplasmic reticulum, calnexin, myelin glycoproteins
Type of item
Degree grantor
University of Alberta
Author or creator
Jung, Joanna
Supervisor and department
Michalak, Marek (Biochemistry)
Examining committee member and department
Todd, Kathryn (Psychiatry)
Posse de Chaves, Elena (Pharmacology)
Lemire, Bernard (Biochemistry)
Eggleton, Paul (Medicine and Dentistry)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
ABSTRACT Endoplasmic reticulum (ER) plays an essential role in the proper folding, maturation and quality control of newly synthesized membrane and secretory proteins. The ER contains molecular chaperones and unique enzymes that assist in protein folding and catalyze co- and post-translational modifications. The two homologous ER chaperones, calnexin and calreticulin are key components of the quality control in the secretory pathway. These chaperones are also involved in mediating interactions between newly synthesized proteins and ERp57, a thiol-disulfide oxidoreductase catalyzing disulfide bond formation and isomerization. Deletion of calreticulin or ERp57 in mice leads to an early death in utero, surprisingly, deficiency in calnexin is not embryonic lethal and results in a phenotype that includes alterations in morphology of myelin of peripheral and central nervous systems. Two important glycoproteins of compact peripheral myelin that are involved in its formation and maintenance are P0 and PMP22. Many of the mutations within P0 and PMP22 genes are associated with human hereditary neuropathies. In this study we created calreticulin-, ERp57- and calnexin-deficient cell lines stably expressing myelin glycoproteins and used them to investigate the role of ER chaperones calnexin, calreticulin and ERp57 in expression, cellular trafficking, proper folding and function of myelin specific glycoproteins. We showed novel interaction between P0 and calnexin as well as myelin oligodendrocyte glycoprotein (MOG) and calnexin. Moreover, we investigated cellular trafficking of myelin glycoproteins and discovered that P0, PMP22 and MOG localize to the plasma membrane in all cell types tested. However, the adhesive function of P0 and PMP22 was compromised in the absence of calnexin or ERp57. Limited trypsin digestion of PMP22 and P0 revealed that the cell surface targeted myelin proteins were misfolded when expressed in calnexin- or ERp57-deficient cells. We also show that expression of myelin glycoproteins in the absence of ER chaperones does not induce endoplasmic reticulum stress. Research presented in this thesis highlights the diversity of the roles of ER chaperones calnexin, ERp57 and calreticulin in the maturation of major myelin glycoproteins.
License granted by Joanna Jung ( on 2011-09-15T17:17:00Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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