Iron accumulates in brain regions that undergo degeneration in several neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease (PD) (1-3). 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 iron mismanagement may be involved in neurodegeneration. We have previously described a neurodegenerative disease that we named hereditary ferritinopathy (HF) which is caused by mutations in the ferritin light polypeptide (FTL) gene. HF is a severe movement disorder neuropathologically characterized by abnormal accumulation of iron and ferritin throughout the CNS (4). We propose that the two key toxic pathologic mechanisms implicated in the development of HF are i) a gain of a toxic function of ferritin and ii) a loss of the normal function of ferritin. A key question is whether these mechanisms are acting independently or together to lead to HF. In the present application, we will develop two novel conditional cell-specific ferritin knockouts that will allow us to determine whether a loss of function of ferritin is merely associated with the disease process or a causative agent in the disease. By using specific promoters, these models will allow us to study the consequences of a loss of the ferroxidase activity of ferritin (Fth1 gene) and/or the loss of the iron storage function of ferritin (Ftl gene) in discrete cell populations in the CNS without affecting iron metabolism in other organ systems. Currently, there are no in vivo models in which to study the consequences of a loss of function of ferritin. The animal models developed in this application will solve this problem, will allow the examination of ferritin malfunction in cells of the CNS, and will circumvent the embryonic lethality known to occur in Fth1 knock-out mice (5,6). In order to test our hypothesis, our specific aims are:
Specific Aim 1 : To conditionally knock-out (cKO) the murine Fth1 and the Ftl genes in discrete cell populations of the CNS to determine whether misregulation of iron metabolism in affected cells is implicated as a cause of neurodegeneration In these cKO mice, loss of function of ferritin will be targeted to neurons or glia, the two population of cells that degenerate in HF, using specific promoters expressing the CreERT2 protein. Importantly, ferritin loss of function could be achieve in other cell populations or organ systems using our """"""""floxed"""""""" ferritin mice in combination with transgenic mice expressing the CreERT2 protein under the control of specific promoters.

Public Health Relevance

Abnormal iron metabolism has been suggested to contribute to the development of several neurodegenerative diseases, like Alzheimer disease and Parkinson disease. We propose to develop new mouse models that will allow a detail in vivo analysis of the interaction of normal aging, abnormal brain iron metabolism and neurodegeneration. Importantly, these new animal models may be also useful for the study of iron metabolism in different organ systems and in association with a variety of iron-related diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-BDCN-M (07))
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Sutherland, Margaret L
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Garringer, Holly J; Irimia, Jose M; Li, Wei et al. (2016) Effect of Systemic Iron Overload and a Chelation Therapy in a Mouse Model of the Neurodegenerative Disease Hereditary Ferritinopathy. PLoS One 11:e0161341
Li, Wei; Garringer, Holly J; Goodwin, Charles B et al. (2015) Systemic and cerebral iron homeostasis in ferritin knock-out mice. PLoS One 10:e0117435
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
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
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
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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
Deng, Xiaoling; Vidal, Ruben; Englander, Ella W (2010) Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy. Neurosci Lett 479:44-8