Galactosyl-ceramidase (GALC) is a ubiquitous lysosomal enzyme crucial for the correct myelination of the mammalian nervous system during early postnatal development. However, the physiological consequence of GALC deficiency in the adult brain remains unknown. In this study, we found that mice with conditional ablation of GALC activity in post-myelinating oligodendrocytes were lethally sensitized when challenged with chronic experimental allergic encephalomyelitis (EAE), in contrast with the non-lethal dysmyelination observed in ablated mice without the EAE challenge. Mechanistically, we found strong inflammatory demyelination without remyelination and an impaired fusion of lysosomes and autophagosomes with accumulation of myelin debris after a transcription factor EB-dependent increase in the lysosomal autophagosome flux. These results indicate that the physiological impact of GALC deficiency is highly influenced by the cell context (oligodendroglial vs. global expression), the presence of inflammation, and the developmental time when it happens (pre-myelination vs. post-myelination). We conclude that expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to decrease vulnerability to additional demyelinating insults.

中文翻译：

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成人少突胶质细胞中半乳糖基神经酰胺酶的缺乏会使慢性实验性过敏性脑脊髓炎的疾病严重程度恶化


半乳糖基神经酰胺酶 (GALC) 是一种普遍存在的溶酶体酶，对于产后早期发育过程中哺乳动物神经系统的正确髓鞘形成至关重要。然而，成人大脑中 GALC 缺乏的生理后果仍不清楚。在这项研究中，我们发现，在髓鞘形成后少突胶质细胞中条件性去除 GALC 活性的小鼠在受到慢性实验性过敏性脑脊髓炎 (EAE) 攻击时会出现致命性致敏，而在没有接受 EAE 攻击的去除小鼠中观察到的非致命性髓鞘形成障碍则相反。从机制上讲，我们发现，在转录因子 EB 依赖性的溶酶体自噬体通量增加后，存在强烈的炎症性脱髓鞘作用，但没有髓鞘再生，并且溶酶体和自噬体的融合受损，髓磷脂碎片积累。这些结果表明，GALC 缺乏的生理影响很大程度上受到细胞环境（少突胶质细胞表达与整体表达）、炎症的存在以及炎症发生的发育时间（髓鞘形成前与髓鞘形成后）的影响。我们得出的结论是，成人少突胶质细胞中的表达对于维持成人中央髓鞘质和降低对额外脱髓鞘损伤的脆弱性至关重要。