Increased interactions and engulfment of dendrites by microglia precede Purkinje cell degeneration in a mouse model of Niemann Pick Type-C

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.

NPC1 deficiency impairs cerebellar postnatal development of microglia and climbing fiber refinement in a mouse model of Niemann-Pick Type C disease

“…Previous work in our laboratory showed significant changes in microglia number, morphology and phagosome content in the cerebellum of Npc1 nmf164 mice at post-weaning age and before PC degeneration (Kavetsky et al, 2019). Interestingly, the migration, proliferation and differentiation of cerebellar microglia occur postnatally along with the development and differentiation of cerebellar neurons.…”

“…Interestingly, recent studies have shown that genetic inactivation of reactive microglia in Npc1 −/− mice reduces neurological impairment and increases their life span (Cougnoux et al, 2018). We recently found that engulfment and phagocytosis of dendrites by activated microglia occur early and precede PC loss in NPC (Kavetsky et al, 2019), demonstrating that activated microglia contribute to PC degeneration in NPC.…”

Shedding Light on the Dark Side of the Microglia

“…Another condition, a mouse model of Niemann-Pick type C, where neurodegeneration and inflammation are found, revealed the presence of the DM. Indeed, Kavetsky et al (2019) investigated NPC nmf164 mice given for 5 weeks either a Western diet or a regular diet. Niemann-Pick type C is a genetic condition with mutations in the NPC genes (Npc1/2), which most notably lead to dysfunctional lysosomes (Wheeler and Sillence, 2019).…”

Neuropathophysiology of Lysosomal Storage Diseases: Synaptic Dysfunction as a Starting Point for Disease Progression

“…Moreover, HS fragments enhance integrin-based focal adhesions formation and activation in normal mouse astrocytes or in human neuronal progenitors, resulting in cell polarization and migration defects [43]. In the Npc1 -/mice, the mouse model of Niemann Pick type C 1 (NPC1), microglia contribute to the degeneration of Purkinje cells by engulfing and destroying their dendrites [44]. The same study also reported that microglia accumulated phagosomes and autofluorescent material that coincided with the degeneration of dendrites and Purkinje cells.…”