title: Attenuation of endoplasmic reticulum stress in Pelizaeus-Merzbacher disease by an anti-malaria drug, chloroquine.
abstract: Pelizaeus-Merzbacher disease (PMD) is a hypomyelinating disorder caused by the duplication and missense mutations of the proteolipid protein 1 (PLP1) gene. PLP1 missense proteins accumulate in the endoplasmic reticulum (ER) of premature oligodendrocytes and induce severe ER stress followed by apoptosis of the cells. Here, we demonstrate that an anti-malaria drug, chloroquine, decreases the amount of an ER-resident mutant PLP1 containing an alanine-243 to valine (A243V) substitution, which induces severe PMD in human. By preventing mutant PLP1 translation through enhancing the phosphorylation of eukaryotic initiation factor 2 alpha, chloroquine ameliorated the ER stress induced by the mutant protein in HeLa cells. Chroloquine also attenuated ER stress in the primary oligodendrocytes obtained from myelin synthesis deficit (msd) mice, which carry the same PLP1 mutation. In the spinal cords of msd mice, chloroquine inhibited ER stress and upregulated the expression of marker genes of mature oligodendrocytes. Chloroquine-mediated attenuation of ER stress was observed in HeLa cells treated with tunicamycin, an N-glycosylation inhibitor, but not with thapsigargin, a sarco/ER Ca(2+)ATPase inhibitor, which confirms its efficacy against ER stress caused by nascent proteins. These findings indicate that chloroquine is an ER stress attenuator with potential use in treating PMD and possibly other ER stress-related diseases.
authors: 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, Japan.
authors: Toshifumi
authors: T
authors: Morimura
authors: Yurika
authors: Y
authors: Numata
authors: Shoko
authors: S
authors: Nakamura
authors: Eriko
authors: E
authors: Hirano
authors: Leo
authors: L
authors: Gotoh
authors: Yu-ich
authors: YI
authors: Goto
authors: Makoto
authors: M
authors: Urushitani
authors: Ken
authors: K
authors: Inoue
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000188:drug therapy* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism
chemical_list: D000962:Antimalarials; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D002738:Chloroquine
keywords: ER stress; PLP; PMD; UPR; chloroquine; treatment