Department of Molecular & Cellular Biosciences, Rowan University, Glassboro, NJ, USA.
The Jackson Laboratory, Bar Harbor, ME, USA.
Sci Rep. 2019 Oct 11;9(1):14722. doi: 10.1038/s41598-019-51246-1.
Niemann Pick Type-C disease (NPC) is an inherited lysosomal storage disease (LSD) caused by pathogenic variants in the Npc1 or Npc2 genes that lead to the accumulation of cholesterol and lipids in lysosomes. NPC1 deficiency causes neurodegeneration, dementia and early death. Cerebellar Purkinje cells (PCs) are particularly hypersensitive to NPC1 deficiency and degenerate earlier than other neurons in the brain. Activation of microglia is an important contributor to PCs degeneration in NPC. However, the mechanisms by which activated microglia promote PCs degeneration in NPC are not completely understood. Here, we are demonstrating that in the Npc1 mouse cerebellum, microglia in the molecular layer (ML) are activated and contacting dendrites at early stages of NPC, when no loss of PCs is detected. During the progression of PCs degeneration in Npc1 mice, accumulation of phagosomes and autofluorescent material in microglia at the ML coincided with the degeneration of dendrites and PCs. Feeding Npc1 mice a western diet (WD) increased microglia activation and corresponded with a more extensive degeneration of dendrites but not PC somata. Together our data suggest that microglia contribute to the degeneration of PCs by interacting, engulfing and phagocytosing their dendrites while the cell somata are still present.
尼曼匹克 C 型病（NPC）是一种遗传性溶酶体贮积病（LSD），由 NPC1 或 NPC2 基因的致病性变异引起，导致溶酶体中胆固醇和脂质的积累。NPC1 缺乏会导致神经退行性变、痴呆和早逝。小脑浦肯野细胞（PCs）对 NPC1 缺乏特别敏感，比大脑中的其他神经元更早退化。小胶质细胞的激活是 NPC 中 PCs 退化的重要贡献者。然而，激活的小胶质细胞如何促进 NPC 中 PCs 退化的机制尚不完全清楚。在这里，我们证明在 Npc1 小鼠小脑，分子层（ML）中的小胶质细胞在 NPC 的早期阶段被激活并与树突接触，此时未检测到 PCs 的丢失。在 Npc1 小鼠 PCs 退化的进展过程中，ML 中小胶质细胞中吞噬体和自荧光物质的积累与树突和 PCs 的退化同时发生。用西方饮食（WD）喂养 Npc1 小鼠会增加小胶质细胞的激活，并与更广泛的树突退化相关，但与 PC 细胞体无关。我们的数据表明，小胶质细胞通过与树突相互作用、吞噬和吞噬它们的树突来促进 PCs 的退化，而细胞体仍然存在。
