Iron accumulates in brain regions that undergo degeneration in several neurodegenerative diseases such as Alzheimer disease and Parkinson disease. However, the precise role of iron in the neurodegenerative process is unclear. The long term goals of this project are to identify and characterize the mechanism(s) by which abnormal iron metabolism may be involved in neurodegeneration. We recently characterized the neurodegenerative disease hereditary ferritinopathy (HF), which is caused by mutations in the ferritin light polypeptide (FTL) gene. HF is a movement disorder that is neuropathologically characterized by abnormal accumulation of ferritin inclusion bodies (IBs) and iron throughout the CNS (Vidal 2011). Since abnormal iron metabolism in HF is directly linked to neurodegeneration, the study of this disease has far- reaching implications beyond this single gene disorder. During the previous funding period, we characterized the biochemical composition of IBs in HF, identified the structural defect that leads to iron overload and IB formation, and developed and characterized the only available animal model for HF. Based on our previous work, we proposed that the two key toxic pathologic mechanisms implicated in the development of HF are i) a loss of the normal function of ferritin and ii) a gain of a toxic functin of ferritin. A key question is whether these mechanisms are acting independently or together to lead to neurodegeneration in HF. Ferritin composed by mutant FTL subunits show disruption of ferritin 4-fold pores and unraveling and extension of the C-terminal peptide. We hypothesize that these structural problems cause ferritin malfunction, generation of free hydroxyl radicals, iron-catalyzed oxidation of ferritin, and IB formation. In addition, since ferritin malfunction leads to deranged iron metabolism, we propose that modulation of iron levels in the CNS could delay (and perhaps stop) the progression of the disease. In order to test our hypotheses, our specific aims are:
Specific Aim 1 : to establish that iron bridging is the common mechanism leading to IB formation in HF and that the disruption of ferritin 4-fold pores is the common event that leads to ferritin malfunction and oxidative modification of ferritin.
Specific Aim 2 : to characterize ferritn loss-of function and ferritin gain of toxic function using cellular models based on the expression of the HF-associated p.Phe167SerfsX26 polypeptide and the genetic reduction of ferritin Ftl polypeptide synthesis.
Specific Aim 3 : To characterize in vivo the consequences of the loss of the iron storage function of ferritin in the CNS and investigate the role of iron in the pathophysiology of HF.

Public Health Relevance

This project will investigate the role of iron in the neurodegenerative disease hereditary ferritinopathy, in which abnormal iron metabolism is directly linked to neurodegeneration. We will perform a series of in vitro experiments to determine the molecular basis of HF and use animal models to perform in vivo studies to gain additional knowledge on the basis of the disease and to test some form of therapy. Our work will provide new insights into the role of abnormal iron metabolism in neurodegeneration.

National Institute of Health (NIH)
Research Project (R01)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Sieber, Beth-Anne
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Nishida, Katsuya; Garringer, Holly J; Futamura, Naonobu et al. (2014) A novel ferritin light chain mutation in neuroferritinopathy with an atypical presentation. J Neurol Sci 342:173-7
Marcora, María S; Fernández-Gamba, Agata C; Avendaño, Luz A et al. (2014) Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia. Mol Neurodegener 9:5
Garringer, Holly J; Murrell, Jill; Sammeta, Neeraja et al. (2013) Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice. PLoS One 8:e56426
Vidal, Ruben; Sammeta, Neeraja; Garringer, Holly J et al. (2012) The Psen1-L166P-knock-in mutation leads to amyloid deposition in human wild-type amyloid precursor protein YAC transgenic mice. FASEB J 26:2899-910
Baraibar, Martin A; Barbeito, Ana G; Muhoberac, Barry B et al. (2012) A mutant light-chain ferritin that causes neurodegeneration has enhanced propensity toward oxidative damage. Free Radic Biol Med 52:1692-7
Farrow, Emily G; Yu, Xijie; Summers, Lelia J et al. (2011) Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice. Proc Natl Acad Sci U S A 108:E1146-55
Muhoberac, Barry B; Baraibar, Martin A; Vidal, Ruben (2011) Iron loading-induced aggregation and reduction of iron incorporation in heteropolymeric ferritin containing a mutant light chain that causes neurodegeneration. Biochim Biophys Acta 1812:544-8
Vidal, Ruben; Ghetti, Bernardino (2011) Characterization of amyloid deposits in neurodegenerative diseases. Methods Mol Biol 793:241-58
Garringer, Holly J; Murrell, Jill; D'Adamio, Luciano et al. (2010) Modeling familial British and Danish dementia. Brain Struct Funct 214:235-44
Baraibar, Martin A; Muhoberac, Barry B; Garringer, Holly J et al. (2010) Unraveling of the E-helices and disruption of 4-fold pores are associated with iron mishandling in a mutant ferritin causing neurodegeneration. J Biol Chem 285:1950-6

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