The machanism of oligodendroglial apoptosis of in the model of the genetic demyelination.

抽搐小鼠是人类克拉伯病的真实模型，其由半乳糖神经酰胺酶缺乏引起。在本研究中，我们首次发现，少突胶质细胞的数量进行性减少，导致脱髓鞘在出生后的第30天CNS中，少突胶质细胞的凋亡判断的形态学标准，以及存在TUNEL阳性的少突胶质细胞和DNA梯状。然而，脊髓中的少突胶质细胞可能通过坏死途径而非凋亡途径导致细胞死亡。因此，即使基本缺陷是所有抽搐少突胶质细胞共有的，环境因素也可能决定它们最终死亡的途径。我们还认识到，TNF-α，一种体外成熟的凋亡分子，随着抽搐脑中脱髓鞘的进展而表达，而TNF-α在年龄匹配的正常对照中不表达。双标记结果显示，TNF-α表达于抽搐脑内活化的小胶质细胞/巨噬细胞，尤其是小脑白色质和桥小脑角。这些部位严重脱髓鞘，有大量凋亡的少突胶质细胞。这些证据表明，这些病变中的少突胶质细胞凋亡是通过TNF-α介导的途径进行的。我们正在研究TNF-α诱导活化的小胶质细胞后的下游级联反应，了解少突胶质细胞死亡的确切机制，可能为这种遗传性脱髓鞘提供合理的治疗方法。

The twitcher mouse is an authentic model of a human Krabbe disease, which is caused by the deficiency of galactosylceramidase. After postnatal day 30, the number of oligodendroglia progressive decreased with resultant demyelination in the CNS.In this study, we first found out that oligodendroglia in the twitcher cerebrum were depleted by apoptosis judgeby the morphological criteria as well as the presence of TUNEL-positive oligodendroglia and DNA laddering. However, oligodendroglia in the spinal cord was suggested to take a necrotic pathway rather than apoptosis leading to the cell death. Thus, even if thebasic defect is common to all twitcher oligodendroglia, the environmental factors may decide what pathways they take to the eventual death.We also recognized that TNF-α, a well-established apoptotic molecule in vitro, became expressed in concordance with the progression of demyelination in the twitcher brains, whereas TNF-α is not expressed in the age-matched normal controls. Double labeling revealed that TNF-α was expressed in activated microglia/macrophages in the twitcher brains, especially in the cerebellar white matter and the cerebellopontine angle. These sites were severely demyelinated with a lot of apoptotic oligodendrocytes. These lines of evidence indicated that the apoptosis of oligodendroglia in these lesions was progressed via the TNF-α-mediated pathway. We are now investigating the downstream cascade following the TNF-α induction in activated microglia.To know the exact mechanism how oligodendroglia die may make the rational therapy available for this genetic demyelination.