Endoplasmic reticulum stress in PLP-overexpressing transgenic rats: gray matter oligodendrocytes are more vulnerable than white matter oligodendrocytes.
Studies dealing with transport of proteins from the oligodendrocyte cell body to the myelin sheath reveal the presence of different transport pathways. Proteolipid protein (PLP) is synthesized at the rough endoplasmic reticulum (ER) and then processed through the Golgi apparatus and transported to the myelin membranes. Myelin basic protein (MBP) on the other hand is synthesized locally at the ends of cell processes where its messenger RNA is translated on free ribosomes. Here we show that in rats that overexpress PLP, impairment of PLP transport from the cell body to the processes interferes with the translocation of other membrane proteins such as myelin-associated glycoprotein (MAG) and myelin oligodendrocyte glycoprotein (MOG), but not with peripherally translated MBP. In addition, it also impedes the transport of non-myelin proteins, for example the amyloid precursor protein (APP). At the ultrastructural level, the ER of these metabolically disturbed oligodendrocytes revealed extreme swelling of the cisternae, and immunohistochemistry revealed intense expression of the ER chaperone molecule BiP/GRP78 and ER folding enzyme protein disulfide isomerase (PDI). These features suggest that these oligodendrocytes, which were found exclusively in gray matter areas of the spinal cord, started an unfolded protein response while suffering from ER stress. Some of these disturbed oligodendrocytes were seen to undergo programmed cell death. These results indicate that gray matter oligodendrocyte differ from white matter oligodendrocytes in their capacity to stabilize metabolic disturbances by an unfolded protein response.
Bauer
Jan
J
Division of Neuroimmunology, Brain Research Institute, University of Vienna, Austria.
Bradl
Monika
M
Klein
Matthias
M
Leisser
Marianne
M
Deckwerth
Thomas L
TL
Wekerle
Hartmut
H
Lassmann
Hans
H
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D008856:Microscopy, Fluorescence; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000737:chemistry / Q000502:physiology* / Q000648:ultrastructure; D017510:Protein Folding; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000378:metabolism / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C571328:Mog protein, rat; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein