Until now, seven mutations responsible for NF were identified. The H chain has a ferroxidase activity that is necessary for ferric iron incorporation, while the L-chain assists and facilitates the nucleation of the ferric iron inside the cavity ( Arosio and Levi, 2010). The cytosolic ferritin is composed of 24 subunits that co-assemble in heteropolymers of H- and L-chains.
#Ftl mouse acceleration free#
NF is a rare autosomal dominant disease caused by mutations in exons 3 and 4 of the ferritin light chain ( FTL) gene ( Curtis et al., 2001, Muhoberac and Vidal, 2013).įerritin is an iron storage protein able to detoxify cells from the redox-active free iron, that exists in a prevalent cytosolic form and in a minor mitochondrial one ( Arosio and Levi, 2010). It is classified as an adult-onset extrapyramidal disorder, in which motor symptoms prevail, while cognitive decline is uncommon or very mild. Neuroferritinopathy (NF) (or NBIA3, OMIM, 606159) belongs to this group of diseases. An opportunity to investigate the iron involvement in neurodegenerative processes is the group of diseases, referred to as “Neurodegeneration with Brain Iron Accumulation” (NBIA) ( Dusek and Schneider, 2012), in which diagnostic imaging and autopsy findings reveal focal iron accumulation in specific regions of the brain. Iron dyshomeostasis is often associated with neurodegenerative diseases ( Rouault, 2013, Vidal et al., 2008), however whether it is a primary cause of the neurodegenerative process or a secondary effect is still debated ( Levi and Finazzi, 2014). Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy. Our data show that our 498–499InsTC mouse models recapitulate early pathological and clinical traits of the human neuroferritinopathy, thus providing a valuable model for the study of the disease.
Rotarod test revealed a progressive impaired motor coordination building up with age, FTL mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum.
Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Furthermore, post-natal hippocampal neurons obtained from these mice experienced a marked increased cell death in response to chronic iron overload and/or acute oxidative stress, in comparison to wild-type neurons. Nevertheless, also these mice showed oxidative alterations in the brain. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Notably, the accumulation of iron–ferritin bodies was accompanied by signs of oxidative damage. Transgenic mice in the FVB background showed high accumulation of the mutated ferritin in brain where it correlated with increased iron deposition with age, as scored by magnetic resonance imaging. In order to analyze the impact of the mutation in vivo, we generated mouse models for the some pathogenic human FTL gene in FVB and C57BL/6J strains. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. We studied the 498–499InsTC mutation which causes the substitution of the last 9 amino acids and an elongation of extra 16 amino acids at the C-terminus of L-ferritin peptide. It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene ( FTL).