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Hikeshi-Mediated Nuclear Translocation of HSP70 Promotes Myelinogenesis by Preventing FBXW7-mediated Degradation of Sox10

ABSTRACT: Dysregulation of nucleocytoplasmic transport is intensively linked to many neurological diseases. Heat shock proteins 70 (HSP70s), which dramatically change its cellular localization upon stress, play important regulatory roles in nervous system. How the localization of HSP70s is regulated and the underlying physiological functions of this translocation are both poorly understood. Mutation in Hikeshi, encoding a nonconventional nuclear import carrier of HSP70s, lead to inherited leukodystrophy; however, the underlying mechanisms remain poorly understood. Here we showed that Hikeshi and HSP70s are essential for proper CNS myelination and remyelination. Loss of Hikeshi resulted in oligodendrocyte maturation arrest through preventing the nuclear translocation of HSP70s upon oligodendrocyte differentiation. HSP70s interacted with Sox10SOX10 in the nucleus and protected it from E3 ubiquitin ligase FBXW7-mediated ubiquitination degradation. Importantly, we discovered that the Hikeshi-dependent hyperthermia therapy, which induces nuclear import of HSP70s, promoted oligodendrocyte differentiation and remyelination following in vivo demyelinating injury. Overall, we demonstrate that Hikeshi-dependent nuclear translocation of HSP70s is essential for oligodendrocyte differentiation and myelinogenesis, and suggest the potential therapeutic value of hyperthermia therapy in myelin repair.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE225577 | GEO | 2023/02/19

REPOSITORIES: GEO

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Project description:Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients. RNA sequencing of oligodendrocyte progenitor cells treated with vehicle, miconazole or clobetasol for 0, 2, 6, or 12 hours. Cells were plated 1.5 hours prior to addition of drug.

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Hikeshi-Mediated Nuclear Translocation of HSP70 Promotes Myelinogenesis by Preventing FBXW7-mediated Degradation of Sox10

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