Abstract
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 Npc1nmf164 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 Npc1nmf164 mice, accumulation of phagosomes and autofluorescent material in microglia at the ML coincided with the degeneration of dendrites and PCs. Feeding Npc1nmf164 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.
Highlights
The pathophysiology of Niemann Pick Type-C disease (NPC) includes liver dysfunction, splenomegaly, neurodegeneration, dementia, and early death[1,2]
Abnormal and uncoordinated movements are hallmarks of cerebellar degeneration, to be able to determine asymptomatic, pre-symptomatic and symptomatic stages in the Npc1nmf[164] mouse model, two behavioral tests that required motor coordination were performed at 4, 8 and 12 weeks of age. These ages were selected to cover the critical period of time of the disease onset and progression in the Npc1nmf[164] mouse, which occur between post-weaning age and 14wks old, which is the average life-span of this mouse strain
The number of buried marbles significantly increased with age in WT mice, whereas in Npc1nmf[164] mice, significantly fewer marbles were buried at 12 wks of age when compared to 12 wks-WT and 4 wks-Npc1nmf[164] mice (Fig. 1d)
Summary
The pathophysiology of NPC includes liver dysfunction, splenomegaly, neurodegeneration, dementia, and early death[1,2]. The majority of NPC cases are diagnosed at late infantile ages[3] Neurological symptoms such as clumsiness, vertical gaze palsy, and gait disturbances occur as a result of early cerebellar PCs degeneration[4]. It is possible that the death of PCs by necroptosis in NPC promotes and amplifies neuroinflammation, which could accelerate the degeneration of stressed, but otherwise live neurons, during the progression of the disease. Genetic inhibition of microglia activation in Npc1nih mice, delays disease progression and increases mouse survival time by 15%20, suggesting that activated microglia in NPC could contribute to the degeneration of PCs by phagocytosing stressed or damaged cells. We investigated the timing and extent of PCs degeneration in relation to microglia activation, and the correlation of these phenotypes to motor deficits in the Npc1nmf[164] mouse.
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