Several neurodegenerative diseases are recognized as disorders of abnormal protein conformation. Many of them arise from mutations that result in a protein with decreased conformational stability that prevents the normal folding or the association of the polypeptide with other subunits or stabilizing cofactors. We described a neurodegenerative disease characterized by the presence of intranuclear ferritin inclusion bodies associated with a novel mutation in the ferritin light chain (FTL) gene. We hypothesize that the mutation causes a major conformational change in the FTL polypeptide, leading to the abnormal accumulation of ferritin inclusion bodies and neurodegeneration. Our long-term objective is to define the structural basis and mechanisms that are implicated in the formation of ferritin inclusion bodies and in the neurodegenerative process. This work has far-reaching implications beyond this single gene disorder, since many other neurodegenerative diseases are also characterized by the presence of intranuclear inclusion bodies. Furthermore, these studies will increase our understanding of the consequences of the disruption of cellular iron metabolism in more common neurodegenerative diseases.
In Specific Aim 1, we will determine the consequences of the mutation in the stability of the FTL subunit as well as in the assemble and functionality of ferritin. Detail biochemical analysis will provide the basis to understand the role of the mutation in the disease.
In Specific Aim 2, we will determine the temporal and spatial patterns of ferritin deposition in brain tissues from transgenic mice and determine whether misregulation of iron metabolism in affected neurons is implicated as a cause of neurodegeneration. These studies will provide insights on basic pathological mechanisms.
In Specific Aim 3, we will determine whether mutant ferritin gains a toxic function that is harmful to neurons. We will study the interaction between ferritin and nuclear proteins and the role of the ubiquitin-proteasome pathway in the abnormal accumulation of ferritin and in the pathogenesis of the disease. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CDIN (01))
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Sieber, Beth-Anne
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Indiana University-Purdue University at Indianapolis
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United States
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Garringer, Holly J; Sammeta, Neeraja; Oblak, Adrian et al. (2017) Amyloid and intracellular accumulation of BRI2. Neurobiol Aging 52:90-97
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
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
Vidal, Rubén; Ghetti, Bernardino (2012) Generation of a novel murine model of A? deposition based on the expression of human wild-type amyloid precursor protein gene. Prion 6:346-9
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

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