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.

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

“…Many of these parameters had a similar direction of change between affected mice and human patients, with some in the latter group being at the low side of the normal range [93]. These findings indicated that Niemann-Pick type C1 disease causes dysregulation of iron homeostasis, including hematological alterations [93]. Consistent with these findings, a 2-year-old patient with Niemann-Pick type C had low blood iron with microcytosis [94].…”

“…Alterations were observed across a variety of iron-related parameters in samples from both mice and humans with Niemann-Pick type C1 disease [93]. Examples of parameters that were affected include lower hematocrit, lower corpuscular hemoglobin and volume, lower levels of iron and light chain ferritin, and increased levels of soluble transferrin receptor in the serum of affected mice [93]. Many of these parameters had a similar direction of change between affected mice and human patients, with some in the latter group being at the low side of the normal range [93].…”

“…Examples of parameters that were affected include lower hematocrit, lower corpuscular hemoglobin and volume, lower levels of iron and light chain ferritin, and increased levels of soluble transferrin receptor in the serum of affected mice [93]. Many of these parameters had a similar direction of change between affected mice and human patients, with some in the latter group being at the low side of the normal range [93]. These findings indicated that Niemann-Pick type C1 disease causes dysregulation of iron homeostasis, including hematological alterations [93].…”

Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST

“…41 Previous studies have described an imbalance of iron metabolism and haematological abnormalities in NPC1 mouse models and in patients with Niemann-Pick disease type C1. 42 Further studies are required to understand the extent to which an inability to promote iron mobilization by autophagy and concomitant effects on mitochondrial function are linked with defects observed in patients. The platform we have described here and its application to relevant cell lineages linked with LSDs may facilitate identification of molecular defects or pathways with relevance to disease.…”

Why Is Iron Deficiency/Anemia Linked to Alzheimer’s Disease and Its Comorbidities, and How Is It Prevented?

“…In general, dysregulated iron metabolism is associated with cognitive disorders, including memory and attention disorders, and anemia or, at least, an iron deficiency [ 36 , 37 ]. Ferritin levels in the cerebrospinal fluid are associated with inflammation markers, phospho-tau, and apolipoprotein E levels [ 38 ].…”