Soung Allison L, Kyauk Roxanne V, Pandey Shristi, Shen Yun-An A, Reichelt Mike, Lin Han, Jiang Zhiyu, Kirshnamoorthy Praveen, Foreman Oded, Lauffer Benjamin E, Yuen Tracy J
Department of Neuroscience, Genentech Inc, South San Francisco, California, USA.
Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, California, USA.
Glia. 2025 Apr;73(4):773-787. doi: 10.1002/glia.24648. Epub 2024 Nov 27.
Multiple lines of evidence indicate that mitochondrial dysfunction occurs in demyelinating diseases, such as multiple sclerosis (MS). Failure of remyelination is thought to be caused in part by a block of oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes, which generate myelin sheaths around axons. The process of OPC differentiation requires a substantial amount of energy and high demand for ATP which is supplied through the mitochondria. In this study, we highlight mitochondrial gene expression changes during OPC differentiation in two murine models of remyelination and in human postmortem MS brains. Given these transcriptional alterations, we then investigate whether genetic alteration of USP30, a mitochondrial deubiquitinase, enhances OPC differentiation and myelination. By genetic knockout of USP30, we observe increased OPC differentiation and myelination without affecting OPC proliferation and survival in in vitro and ex vivo assays. We also find that OPC differentiation is accelerated in vivo following focal demyelination in USP30 knockout mice. The promotion of OPC differentiation and myelination observed is associated with increased oxygen consumption rates in USP30 knockout OPCs. Together, these data indicate a role for mitochondrial function and USP30 in OPC differentiation and myelination.
多条证据表明，线粒体功能障碍发生在脱髓鞘疾病中，如多发性硬化症（MS）。髓鞘再生失败被认为部分是由于少突胶质前体细胞（OPC）分化为少突胶质细胞受阻所致，少突胶质细胞围绕轴突形成髓鞘。OPC分化过程需要大量能量以及对通过线粒体供应的ATP有很高需求。在本研究中，我们着重介绍了在两种髓鞘再生小鼠模型以及人类多发性硬化症死后大脑中OPC分化过程中线粒体基因表达的变化。鉴于这些转录改变，我们接着研究线粒体去泛素酶USP30的基因改变是否会增强OPC分化和髓鞘形成。通过对USP30进行基因敲除，我们在体外和体内实验中观察到OPC分化和髓鞘形成增加，而不影响OPC的增殖和存活。我们还发现，在USP30基因敲除小鼠局灶性脱髓鞘后，体内OPC分化加速。观察到的OPC分化和髓鞘形成的促进与USP30基因敲除的OPC中氧消耗率增加有关。总之，这些数据表明线粒体功能和USP30在OPC分化和髓鞘形成中发挥作用。
