Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination
Autophagy is essential for oligodendrocyte differentiation, survival, and proper myelination
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DOI：
10.1002/glia.23646
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发表时间：
2019-09-01
期刊：
影响因子：
6.2
通讯作者：
Whittennore, Scott R.
中科院分区：
文献类型：
--
作者：
Bankston, Andrew N.;Forston, Michael D.;Whittennore, Scott R.
髓鞘形成不足是轴突周围高度特化的膜的螺旋包裹，会导致严重的神经疾病。少突胶质前体细胞(OPC)成熟为髓鞘少突胶质细胞(OL)是中枢神经系统(CNS)髓鞘的唯一提供者，其成熟受到严格的调控，并涉及广泛的形态变化。在这里，我们提出的证据表明，自噬，即通过双膜自噬小体有针对性地分离细胞质和细胞器来降解溶酶体，对于OPC/OL的分化、生存和适当的髓鞘发育是必不可少的。自噬活性的显著增加与OL的分化相一致，OL过程的自噬通量增加最大。多条证据表明，在髓鞘从髓鞘运输到OL胞体之前，自噬小体在发育过程中形成。从出生后第5天开始，OPC/OL特异性缺失基本自噬基因ATG5的小鼠出现快速震颤，并在出生后第12天左右死亡。进一步分析发现，OPC细胞凋亡死亡，分化减少，髓鞘形成减少。存活的ATG5(-/-)OL不能产生适当的髓鞘结构。在体外，药物抑制OPC/背根神经节(DRG)共培养的自噬阻止了髓鞘形成，产生了被许多短突起包围的OL。相反，自噬刺激增强了髓鞘形成。这些结果表明自噬是OPC存活、成熟和正常髓鞘形成的关键调节因素。自噬可能为促进OL存活和随后的损伤后髓鞘修复提供一个有吸引力的靶点。
Deficient myelination, the spiral wrapping of highly specialized membrane around axons, causes severe neurological disorders. Maturation of oligodendrocyte progenitor cells (OPC) to myelinating oligodendrocytes (OL), the sole providers of central nervous system (CNS) myelin, is tightly regulated and involves extensive morphological changes. Here, we present evidence that autophagy, the targeted isolation of cytoplasm and organelles by the double-membrane autophagosome for lysosomal degradation, is essential for OPC/OL differentiation, survival, and proper myelin development. A marked increase in autophagic activity coincides with OL differentiation, with OL processes having the greatest increase in autophagic flux. Multiple lines of evidence indicate that autophagosomes form in developing myelin sheathes before trafficking from myelin to the OL soma. Mice with conditional OPC/OL-specific deletion of the essential autophagy gene Atg5 beginning on postnatal Day 5 develop a rapid tremor and die around postnatal Day 12. Further analysis revealed apoptotic death of OPCs, reduced differentiation, and reduced myelination. Surviving Atg5(-/-) OLs failed to produce proper myelin structure. In vitro, pharmacological inhibition of autophagy in OPC/dorsal root ganglion (DRG) co-cultures blocked myelination, producing OLs surrounded by many short processes. Conversely, autophagy stimulation enhanced myelination. These results implicate autophagy as a key regulator of OPC survival, maturation, and proper myelination. Autophagy may provide an attractive target to promote both OL survival and subsequent myelin repair after injury.