Department of Neurology, Section of Developmental Neurobiology, University of Würzburg, Würzburg, Germany.
PLoS One. 2012;7(8):e42554. doi: 10.1371/journal.pone.0042554. Epub 2012 Aug 8.
Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage.
过表达蛋白脂质蛋白（PLP）的小鼠会发展出类似白质营养不良的疾病，涉及细胞毒性 CD8+T 淋巴细胞。在这里，我们表明这些细胞毒性 T 淋巴细胞会破坏逆行轴突运输。我们使用荧光金立体定向注射到上丘，发现少突胶质细胞中的 PLP 过表达导致视网膜神经节细胞轴突的逆行轴突运输显著减少。我们还观察到线粒体在近节段轴突肿胀处积聚，表明轴突运输受到干扰。在没有 T 淋巴细胞的情况下过表达 PLP 可挽救逆行轴突运输缺陷并消除轴突肿胀。将来自野生型小鼠的骨髓转移，而不是来自穿孔素或颗粒酶 B 缺陷突变体的骨髓转移，到淋巴细胞缺陷的 PLP 突变小鼠中，再次导致轴突运输受损和轴突肿胀的形成，这些肿胀主要位于近节段区域。这表明适应性免疫系统，包括释放穿孔素和颗粒酶 B 的细胞毒性 T 淋巴细胞，对于破坏 PLP 转基因疾病模型中的轴突完整性是必要的。基于我们的观察结果，到目前为止，属于免疫系统的分子和细胞参与者应该被认为是理解具有进行性轴突损伤的遗传性髓鞘疾病的发病机制所必需的。
