Abstract
BackgroundNucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). Pathologic examination of patients with HF has shown abnormal ferritin and iron accumulation in neurons and glia in the central nervous system (CNS) as well as in cells of other organ systems, including skin fibroblasts. To gain some understanding on the molecular basis of HF, we characterized iron metabolism in primary cultures of human skin fibroblasts from an individual with the FTL c.497_498dupTC mutation.ResultsCompared to normal controls, HF fibroblasts showed abnormal iron metabolism consisting of increased levels of ferritin polypeptides, divalent metal transporter 1, basal iron content and reactive oxygen species, and decreased levels of transferrin receptor-1 and IRE-IRP binding activity.ConclusionsOur data indicates that HF fibroblasts replicate the abnormal iron metabolism observed in the CNS of patients with HF. We propose that HF fibroblasts are a unique cellular model in which to study the role of abnormal iron metabolism in the pathogenesis of HF without artifacts derived from over-expression or lack of endogenous translational regulatory elements.
Highlights
Nucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF)
Our results reveal that the broad dysfunction of iron homeostasis observed in individuals with HF and in the transgenic animal model of HF is replicated in HF skin fibroblasts
Ferritin polypeptides accumulate in skin fibroblasts expressing mutant FTL Confocal fluorescence microscopy analysis (Figure 1) using abs against the mutant-FTL chain showed that the mutant polypeptide accumulated both in the cytoplasm and in the nucleus of HF fibroblasts (Figure 1e), as previously reported in skin fibroblasts of individuals with HF and transgenic mice [5,16]
Summary
Nucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). Pathologic examination of patients with HF has shown abnormal ferritin and iron accumulation in neurons and glia in the central nervous system (CNS) as well as in cells of other organ systems, including skin fibroblasts. Mammalian ferritin consists of 24 subunits of FTLs and ferritin heavy polypeptides (FTH); the FTH subunit is involved in the rapid detoxification of iron, whereas the FTL subunit facilitates iron nucleation, mineralization, and long-term iron storage [13]. Transgenic expression of the p.Phe167SerfsX26 polypeptide in mice recapitulated several features of the disease, including intracellular formation of ferritin IBs in neurons and glia in the CNS and in cells of other organ systems, including skin fibroblasts [16].
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