Department of Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ 08028, USA.
Swarthmore College, Department of Biology, Swarthmore, PA 19081, USA.
Development. 2020 Aug 3;147(21):dev189019. doi: 10.1242/dev.189019.
Little is known about the effects of NPC1 deficiency in brain development and whether these effects contribute to neurodegeneration in Niemann-Pick disease type C (NPC). Degeneration of cerebellar Purkinje cells occurs at an earlier stage and to a greater extent in NPC; therefore, we analyzed the effect of NPC1 deficiency on microglia and on climbing fiber synaptic refinement during cerebellar postnatal development using the mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. However, the lack of NPC1 in mice significantly affected the early development of microglia by delaying the radial migration, increasing the proliferation and impairing the differentiation of microglia precursor cells during postnatal development. Additionally, increased phagocytic activity of differentiating microglia was observed at the end of the second postnatal week in mice. Moreover, significant climbing fiber synaptic refinement deficits along with an increased engulfment of climbing fiber synaptic elements by microglia were found in mice, suggesting that profound developmental defects in microglia and synaptic connectivity might precede and predispose Purkinje cells to early neurodegeneration in NPC.
关于 NPC1 缺乏对大脑发育的影响，以及这些影响是否导致尼曼-匹克病 C 型（NPC）中的神经退行性变，目前知之甚少。小脑浦肯野细胞的退化在 NPC 中发生得更早，程度更严重；因此，我们使用 小鼠分析了 NPC1 缺乏对小神经胶质细胞和小脑出生后发育过程中攀附纤维突触细化的影响。我们的分析表明，NPC1 缺乏导致小神经胶质细胞的早期表型变化，这些变化与先天免疫反应无关。然而， 小鼠中 NPC1 的缺乏显著影响小神经胶质细胞的早期发育，通过延迟放射状迁移、增加增殖并损害小神经胶质细胞前体细胞在出生后的分化。此外，在 小鼠的第二周末观察到分化的小神经胶质细胞的吞噬活性增加。此外，在 小鼠中发现了明显的攀附纤维突触细化缺陷，以及小神经胶质细胞对攀附纤维突触成分的吞噬增加，这表明小神经胶质细胞和突触连接的严重发育缺陷可能先于 NPC 中浦肯野细胞的早期神经退行性变，并使它们易于发生。
