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

Neurobiology of Disease

Franca Codazzi¹  Sonia Levi¹  Dario Finazzi²  Ottavio Cremona²  Federica Maccarinelli³  Letterio Salvatore Politi³  Giuseppina Di Giacomo⁴  Fabio Grohovaz⁴  Antonella Pagani⁴  Francesca Cirulli⁴  Anna Cozzi⁴  Marco Giorgio⁵  Stefania Rapino⁵  Sara Capoccia⁶ 

[1] Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milano, Italy;Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy;Department of Molecular and Translational Medicine, University of Brescia, Italy;San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milano, Italy;Section of Behavioral Neuroscience, Department of Cell Biology, Istituto Superiore di Sanità, Rome, Italy;Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milano, Italy;

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

DOI  :  

来源: DOAJ

【 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 C57BL/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, FTL 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.

【 授权许可】

Unknown