Browsing by Subject "Apoferritins"

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    Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants
    (Nature, 2020-11-26) Irimia-Dominguez, Jose; Sun, Chen; Li, Kunpeng; Muhoberac, Barry B.; Hallinan, Grace I.; Garringer, Holly J.; Ghetti, Bernardino; Jiang, Wen; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
    The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin's three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin's iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.
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    A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation
    (Elsevier, 2014-07-15) Nishida, Katsuya; Garringer, Holly J.; Futamura, Naonobu; Funakawa, Itaru; Jinnai, Kenji; Vidal, Ruben; Takao, Masaki; Department of Pathology & Laboratory Medicine, IU School of Medicine
    Neuroferritinopathy or hereditary ferritinopathy is an inherited neurodegenerative disease caused by mutations in ferritin light chain (FTL) gene. The clinical features of the disease are highly variable, and include a movement disorder, behavioral abnormalities, and cognitive impairment. Neuropathologically, the disease is characterized by abnormal iron and ferritin deposition in the central nervous system. We report a family in which neuroferritinopathy begins with chronic headaches, later developing progressive orolingual and arm dystonia, dysarthria, cerebellar ataxia, pyramidal tract signs, and psychiatric symptoms. In the absence of classic clinical symptoms, the initial diagnosis of the disease was based on magnetic resonance imaging studies. Biochemical studies on the proband showed normal serum ferritin levels, but remarkably low cerebrospinal fluid (CSF) ferritin levels. A novel FTL mutation was identified in the proband. Our findings expand the genetic and clinical diversity of neuroferritinopathy and suggest CSF ferritin levels as a novel potential biochemical marker for the diagnosis of neuroferritinopathy.