Chen Oscar C W, Siebel Stephan, Colaco Alexandria, Nicoli Elena-Raluca, Platt Nick, Shepherd Dawn, Newman Stephanie, Armitage Andrew E, Farhat Nicole Y, Seligmann George, Smith Claire, Smith David A, Abdul-Sada Alaa, Jeyakumar Mylvaganam, Drakesmith Hal, Porter Forbes D, Platt Frances M
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, Oxfordshire, OX1 3QT, UK.
Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, 20892, USA.
Wellcome Open Res. 2023 Apr 3;7:267. doi: 10.12688/wellcomeopenres.17261.2. eCollection 2022.
: 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. : 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. : Significant changes in mean corpuscular volume and corpuscular hemoglobin were detected in 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 mice and in an NPC1 cellular model. Comparable hematological changes, including low normal serum iron and transferrin saturation and low cerebrospinal fluid ferritin were confirmed in NPC1 patients. : These data suggest loss of iron homeostasis and hematological abnormalities in NPC1 may contribute to the pathophysiology of this disease.
尼曼-皮克病C1型（NPC1）是一种神经退行性溶酶体贮积症，其特征是多种脂质在晚期内体/溶酶体系统中蓄积，以及酸性钙储存减少。溶酶体系统调节铁稳态的关键方面，这促使我们研究NPC1中是否存在血液学异常和铁代谢缺陷。：在一个真实的小鼠模型和一大群NPC患者中评估了与铁相关的血液学参数、全身和组织金属离子以及相关激素和蛋白质水平、特定促炎介质的表达和红细胞吞噬作用。：从小鼠幼年时就检测到平均红细胞体积和平均红细胞血红蛋白有显著变化。在疾病晚期动物中观察到血细胞比容、红细胞分布宽度和血红蛋白变化。还发现全身缺铁、循环中铁调素增加、铁蛋白减少以及促炎细胞因子水平异常。此外，在小鼠和NPC1细胞模型中存在红细胞吞噬作用缺陷的证据。在NPC1患者中证实了类似的血液学变化，包括血清铁和转铁蛋白饱和度略低于正常以及脑脊液铁蛋白降低。：这些数据表明，NPC1中铁稳态的丧失和血液学异常可能促成了该疾病的病理生理学。
