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.
Exp Biol Med (Maywood). 2014 Apr;239(4):489-501. doi: 10.1177/1535370213520108. Epub 2014 Feb 12.
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.
佩利兹-梅茨巴赫病（PMD）是一种脱髓鞘疾病，由蛋白脂质蛋白 1（PLP1）基因的重复和错义突变引起。PLP1 错义蛋白在不成熟的少突胶质细胞的内质网（ER）中积累，并诱导严重的 ER 应激，随后细胞凋亡。在这里，我们证明一种抗疟疾药物氯喹可以减少内质网驻留的突变型 PLP1 的数量，这种突变型 PLP1 含有丙氨酸-243 到缬氨酸（A243V）取代，这会导致人类出现严重的 PMD。通过增强真核起始因子 2α的磷酸化来阻止突变型 PLP1 的翻译，氯喹改善了突变蛋白在 HeLa 细胞中引起的 ER 应激。氯喹还减弱了从髓鞘合成缺陷（msd）小鼠中获得的原代少突胶质细胞中的 ER 应激，这些小鼠携带相同的 PLP1 突变。在 msd 小鼠的脊髓中，氯喹抑制 ER 应激并上调成熟少突胶质细胞的标记基因表达。氯喹在 HeLa 细胞中处理衣霉素（一种 N-糖基化抑制剂）时可以减轻 ER 应激，但不能用 thapsigargin（一种肌浆/内质网 Ca2+-ATPase 抑制剂），这证实了其对新生蛋白引起的 ER 应激的疗效。这些发现表明氯喹是一种内质网应激调节剂，具有治疗 PMD 及其他可能与内质网应激相关疾病的潜力。
