Depletion of molecular chaperones from the endoplasmic reticulum and fragmentation of the Golgi apparatus associated with pathogenesis in Pelizaeus-Merzbacher disease.
Missense mutations in the proteolipid protein 1 (PLP1) gene cause a wide spectrum of hypomyelinating disorders, from mild spastic paraplegia type 2 to severe Pelizaeus-Merzbacher disease (PMD). Mutant PLP1 accumulates in the endoplasmic reticulum (ER) and induces ER stress. However, the link between the clinical severity of PMD and the cellular response induced by mutant PLP1 remains largely unknown. Accumulation of misfolded proteins in the ER generally leads to up-regulation of ER chaperones to alleviate ER stress. Here, we found that expression of the PLP1-A243V mutant, which causes severe disease, depletes some ER chaperones with a KDEL (Lys-Asp-Glu-Leu) motif, in HeLa cells, MO3.13 oligodendrocytic cells, and primary oligodendrocytes. The same PLP1 mutant also induces fragmentation of the Golgi apparatus (GA). These organelle changes are less prominent in cells with milder disease-associated PLP1 mutants. Similar changes are also observed in cells expressing another disease-causing gene that triggers ER stress, as well as in cells treated with brefeldin A, which induces ER stress and GA fragmentation by inhibiting GA to ER trafficking. We also found that mutant PLP1 disturbs localization of the KDEL receptor, which transports the chaperones with the KDEL motif from the GA to the ER. These data show that PLP1 mutants inhibit GA to ER trafficking, which reduces the supply of ER chaperones and induces GA fragmentation. We propose that depletion of ER chaperones and GA fragmentation induced by mutant misfolded proteins contribute to the pathogenesis of inherited ER stress-related diseases and affect the disease severity.
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502; Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574.
Yurika
Y
Numata
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502; Unit for Neurobiology and Therapeutics, Molecular Neuroscience Research Center, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
Toshifumi
T
Morimura
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502.
Shoko
S
Nakamura
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502.
Eriko
E
Hirano
Department of Pediatrics, Tohoku University School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 980-8574.
Shigeo
S
Kure
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502.
Yu-Ich
YI
Goto
Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawahigashi-machi, Kodaira-shi, Tokyo 187-8502. Electronic address: kinoue@ncnp.go.jp.
Ken
K
Inoue
D020816:Amino Acid Motifs; D000818:Animals; D019921:Biotinylation; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D018991:Myelin Proteolipid Protein / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology; D009836:Oligodendroglia / Q000166:cytology; D015388:Organelles / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000378:metabolism*; D021381:Protein Transport; D058767:Protein Unfolding
D018832:Molecular Chaperones; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; C047516:Plp1 protein, mouse