Defective iron homeostasis and hematological abnormalities in Niemann-Pick disease type C1

Abstract

Background: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative lysosomal storage disorder characterized by the accumulation of multiple lipids in the late endosome/lysosomal system and reduced acidic store calcium. The lysosomal system regulates key aspects of iron homeostasis, which prompted us to investigate whether there are hematological abnormalities and iron metabolism defects in NPC1. Methods: Iron-related hematological parameters, systemic and tissue metal ion and relevant hormonal and proteins levels, expression of specific pro-inflammatory mediators and erythrophagocytosis were evaluated in an authentic mouse model and in a large cohort of NPC patients. Results: Significant changes in mean corpuscular volume and corpuscular hemoglobin were detected in Npc1-/- mice from an early age. Hematocrit, red cell distribution width and hemoglobin changes were observed in late-stage disease animals. Systemic iron deficiency, increased circulating hepcidin, decreased ferritin and abnormal pro-inflammatory cytokine levels were also found. Furthermore, there is evidence of defective erythrophagocytosis in Npc1-/- mice and in an in vitro NPC1 cellular model. Comparable hematological changes, including low normal serum iron and transferrin saturation and low cerebrospinal fluid ferritin were confirmed in NPC1 patients. Conclusions: These data suggest loss of iron homeostasis and hematological abnormalities in NPC1 may contribute to the pathophysiology of this disease.

Iron Limitation Restores Autophagy and Increases Lifespan in the Yeast Model of Niemann–Pick Type C1

“…Gene ontology (GO) analysis on biological processes showed an enrichment in proteins related to vesicle and vacuole fusion and organization, ion homeostasis and transport (namely, iron, manganese, and calcium), polyphosphate metabolism, Golgi organization, autophagy, and protein targeting to vacuole ( Figure 2 D and Supplementary Table S3 ). These results suggest that vesicle trafficking pathways and ion homeostasis are altered in yeast cells lacking Ncr1, being consistent with previously reported trafficking defects and calcium/iron dyshomeostasis [ 9 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 42 , 43 , 44 , 46 , 47 , 58 ] and alterations in the expression of lysosomal proteins related to autophagy in NPC [ 27 ]. A previous study with the yeast model also showed that Ncr1 interacts with vacuolar proteins, including the Pmc1 Ca 2+ ATPase and the Fth1 iron transporter.…”

“…A tendency for iron levels to be higher in post-mortem human NPC1 cerebellar tissue and lower in plasma was also observed [ 42 ]. Recently, Chen et al detected lower levels of ferritin in the cerebrospinal fluid of NPC1 patients, consistent with alterations in iron homeostasis in the central nervous system [ 46 ]. Indeed, the authors showed that Npc1 −/− mice and NPC1 patients have significantly reduced serum iron and several hematological changes characteristic of iron deficiency anemia.…”

“…Indeed, the authors showed that Npc1 −/− mice and NPC1 patients have significantly reduced serum iron and several hematological changes characteristic of iron deficiency anemia. A lower expression of L-ferritin and reduced iron levels in the liver of Npc1 −/− mice was also observed together with higher levels of serum ferritin in NPC patients [ 46 ]. NPC1 fibroblasts from patients also exhibit enhanced expression of genes encoding proteins involved in iron homeostasis (ferritin and sideroflexin 1) [ 70 ].…”

“…NPC1 fibroblasts from patients also exhibit enhanced expression of genes encoding proteins involved in iron homeostasis (ferritin and sideroflexin 1) [ 70 ]. However, several studies report a ferritin deficiency in various NPC tissues [ 44 , 46 , 71 , 72 ] and a decrease in FTH1 (H-ferritin) protein levels in NPC1-deficient HeLa cells [ 47 ]. It has been proposed that lower levels of ferritin lead to an excess of unbound iron, thus favoring lipid peroxidation caused by reactive oxygen species (ROS) [ 73 ].…”

“…Mitochondrial dysfunction in NPC has also been associated with calcium cytotoxicity resulting from the activation of the IP3R type 1 in the ER that increases calcium release [ 41 ]. Numerous studies have also shown that iron homeostasis is disrupted in the plasma and tissues of NPC patients and in animal and cell models of this disease [ 42 , 43 , 44 , 45 , 46 , 47 ]. Iron is a redox-active metal that catalyzes the Fenton reaction, in which hydrogen peroxide is converted into highly reactive hydroxyl radicals.…”