Abstract：
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 Galc-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 Galc expression in adult oligodendrocytes is crucial for the maintenance of adult central myelin and to decrease vulnerability to additional demyelinating insults.
摘要：
半乳糖基-神经酰胺酶（GALC）是一种普遍存在的溶酶体酶，对于出生后早期发育期间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缺乏的生理后果仍然未知。在这项研究中,我们发现，在髓鞘化后少突胶质细胞中GALC活性有条件消除的小鼠在受到慢性实验性过敏性脑脊髓炎（EAE）攻击时被致命性致敏，与在无EAE攻击的GALC消融小鼠中观察到的非致死性髓鞘异常相反。机械上,我们发现,在TFEB依赖性溶酶体自噬体通量增加后,溶酶体和自噬体融合受损,髓鞘碎片积聚.这些结果表明，GALC缺乏的生理影响受细胞环境（少突胶质细胞vs全局表达）的高度影响，炎症的存在，以及发生时的发育时间（髓鞘形成前与髓鞘形成后）。我们得出的结论是，成人少突胶质细胞中的GALC表达对于维持成人中央髓鞘和减少对其他脱髓鞘损伤的脆弱性至关重要。
