生物
再髓鞘化
少突胶质细胞
细胞生物学
白质营养不良
髓鞘
中枢神经系统
神经科学
病理
疾病
医学
作者
Ao Li,Daopeng Li,Di Sun,Xueqin Zhang,Wanying Lei,Mei Wu,Qiuying Huang,Ximing Nian,Wenxiu Dai,Xiaoyun Lu,Zhihao Zhou,Yanqin Zhu,Yunshan Xiao,Ling Zhang,Wei Mo,Zhixiong Liu,Liang Zhang
标识
DOI:10.1016/j.devcel.2023.09.002
摘要
Dysregulation of factors in nucleocytoplasmic transport is closely linked to neural developmental diseases. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of heat shock protein 70 family (HSP70s), leads to inherited leukodystrophy; however, the pathological mechanisms remain elusive. Here, we showed that Hikeshi is essential for central nervous system (CNS) myelination. Deficiency of Hikeshi, which is observed in inherited leukodystrophy patients, resulted in murine oligodendrocyte maturation arrest. Hikeshi is required for nuclear translocation of HSP70s upon differentiation. Nuclear-localized HSP70 promotes murine oligodendrocyte differentiation and remyelination after white matter injury. Mechanistically, HSP70s interacted with SOX10 in the nucleus and protected it from E3 ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, these findings demonstrate that Hikeshi-mediated nuclear translocation of HSP70s is essential for myelinogenesis and provide insights into pathological mechanisms of Hikeshi-related leukodystrophy.
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