Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia

Abstract

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in Npc1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, consequences of NPC1 loss on microglial function remain uncharacterized. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in a NPC1-deficient (Npc1 -/-) murine model and patient blood-derived macrophages. We demonstrate enhanced phagocytic uptake and impaired lipid trafficking in Npc1 -/microglia that precede neuronal death. Loss of NPC1 compromises microglial developmental functions as revealed by increased synaptic pruning and deficient myelin turnover. Undigested myelin accumulates within multi-vesicular bodies of Npc1 -/microglia while lysosomal degradation remains preserved. To translate our findings to human disease, we generated novel ex vivo assays using patient macrophages that displayed similar proteomic disease signatures and lipid trafficking defects as murine Npc1 -/microglia. Thus, peripheral macrophages provide a novel promising clinical tool for monitoring disease progression and therapeutic efficacy in NPC patients. Our study underscores an essential role for NPC1 in immune cells and implies microglial therapeutic potential.

Transcriptional landscape of human microglia reveals robust gene expression signatures that implicates age, sex and APOE-related immunometabolic pathway perturbations

“…ME14 co-expression network (Figure 2C) hub genes NPC2, MSR1 and PLAU are also microglial signature genes in our study and known to be involved in microglial functions [36][37][38][39][40]41 .…”

“…ME14 co-expression network (Figure 2c) hub genes NPC2, MSR1 and PLAU are also microglial signature genes in our study and known to be involved in microglial functions [40][41][42][43][44]45 . Several disease-associated microglial (DAM) markers are also present in this network, including CD9, ARAP2 and MYO1E 4,46,47 that are increased with aging, implicating activated microglial lipid localization pathways in aging (Figure 2f).…”

Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition

“…We investigated microglial phagocytosis by an ex vivo assay as already described ( Colombo et al, 2021 ). Briefly, 10 µm brain sections from APPPS1 mice ( Radde et al, 2006 ) were incubated on coverslips with anti-Aβ antibodies (6E10, 5 μg/ml) to stimulate microglia recruitment.…”

Elevated granulocyte-colony stimulating factor and hematopoietic stem cell mobilization in Niemann-Pick type C1 disease

“…The most severe symptom is neurodegeneration, while additional symptoms such as neonatal jaundice, hepatosplenomegaly, cholestasis, liver and pulmonary disease have been reported in a significant number of patients (13). Although neurodegeneration is the most common symptom of NPC disease (14), a high proportion (~ 40-50%) of NPC patients presents with splenomegaly during infancy (12,13). Splenomegaly has been suggested as the first symptom of NPC1 disease before neurological symptoms appear (15).…”