A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits

NEUROBIOLOGY OF DISEASE

卷:81

Article

Maccarinelli, Federica¹  Pagani, Antonella²  Cozzi, Anna^2,3  Codazzi, Franca²  Di Giacomo, Giuseppina³  Capoccia, Sara⁴  Rapino, Stefania⁵  Finazzi, Dario¹  Politi, Letterio Salvatore²  Cirulli, Francesca⁴  Giorgio, Marco⁵  Cremona, Ottavio^2,3  Grohovaz, Fabio^2,3  Levi, Sonia^2,3 

[1] Univ Brescia, Dept Mol & Translat Med, I-25121 Brescia, Italy

[2] Ist Sci San Raffaele, I-20132 Milan, Italy

[3] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[4] Ist Super Sanita, Dept Cell Biol, Sect Behav Neurosci, I-00161 Rome, Italy

[5] European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy

关键词: Neuroferritinopathy;    Neurodegenerative disorder;    Ferritin;    Iron;    Oxidative damage;   

DOI  :  10.1016/j.nbd.2014.10.023

来源: Elsevier

【 摘 要 】

Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. 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. An analysis with cyclic voltammetry on the purified protein showed that this structural modification severely reduces the ability of the protein to store iron. 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 JC57BL/6J strains. 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. Notably, the accumulation of iron-ferritin bodies was accompanied by signs of oxidative damage. In the C57BL/6 background, both the expression of the mutant ferritin and the iron levels were lower than in the FVB strain. Nevertheless, also these mice showed oxidative alterations in the brain. 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. Ultrastructural analyses revealed an accumulation of lipofuscin granules associated with iron deposits, particularly enriched in the cerebellum and striatum of our transgenic mice. Finally, experimental subjects were tested throughout development and aging at 2-, 8- and 18-months for behavioral phenotype. Rotarod test revealed a progressive impaired motor coordination building up with age, Fa mutant old mice showing a shorter latency to fall from the apparatus, according to higher accumulation of iron aggregates in the striatum. 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. Finally, we propose a mechanistic model of lipofuscine formation that can account for the etiopathogenesis of human neuroferritinopathy. (C) 2014 The Authors. Published by Elsevier Inc.

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