title: ER Chaperone BiP/GRP78 Is Required for Myelinating Cell Survival and Provides Protection during Experimental Autoimmune Encephalomyelitis.
abstract: Myelinating cells synthesize large amounts of membrane protein through the secretory pathway, which makes these cells particularly sensitive to perturbations of the endoplasmic reticulum (ER). Ig binding protein (BiP), also known as glucose-regulated protein 78 (GRP78), is a critical ER chaperone that also plays a pivotal role in controlling the cellular response to ER stress. To examine the potential importance of BiP to myelinating cells, we used a conditional knock-out approach to BiP gene inactivation in oligodendrocytes during development, in adulthood, and in response to experimental autoimmune encephalomyelitis (EAE), an animal model of the inflammatory demyelinating disorder multiple sclerosis (MS). During development, mice lacking functional BiP gene expression in oligodendrocytes developed tremors and ataxia and died before reaching maturity. When BiP gene inactivation in oligodendrocytes was initiated in adulthood, the mice displayed severe neurological symptoms including tremors and hind-limb paralysis. The inactivation of BiP in oligodendrocytes during development or in adulthood resulted in oligodendrocyte loss and corresponding severe myelin abnormalities. Mice heterozygous for the oligodendrocyte-specific inactivation of BiP, which were phenotypically normal without evidence of neuropathology, displayed an exacerbated response to EAE that correlated with an increased loss of oligodendrocytes. Furthermore, mice in which the BiP gene was specifically inactivated in developing Schwann cells displayed tremor that progressed to hindlimb paralysis, which correlated with diminished numbers of myelinating Schwann cells and severe PNS hypomyelination. These studies demonstrate that BiP is critical for myelinating cell survival and contributes to the protective response of oligodendrocyte against inflammatory demyelination.
authors.affiliation: Department of Neurology, University of Chicago, Chicago, Illinois 60637.
authors.forename: Yassir
authors.initials: Y
authors.lastname: Hussien
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Robinson
authors.affiliation: Department of Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California 90089.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, and.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of Chicago, Chicago, Illinois 60637, bpopko@neurology.bsd.uchicago.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control*; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D009836:Oligodendroglia / Q000473:pathology* / Q000648:ultrastructure; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000276:immunology; D010525:Peripheral Nerves / Q000473:pathology; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C539791:Bax-inhibiting peptide, BIP; D016207:Cytokines; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717248:Hspa5 protein, mouse; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D009842:Oligopeptides; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D051742:Transcription Factor CHOP; D005620:Freund's Adjuvant; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571338:Cnp protein, mouse
keywords: ER stress; mouse models; protein homeostasis; unfolded protein response