title: Behavioral characterization of mouse models of neuroferritinopathy.
abstract: Ferritin is the main intracellular protein of iron storage with a central role in the regulation of iron metabolism and detoxification. Nucleotide insertions in the last exon of the ferritin light chain cause a neurodegenerative disease known as Neuroferritinopathy, characterized by iron deposition in the brain, particularly in the cerebellum, basal ganglia and motor cortex. The disease progresses relentlessly, leading to dystonia, chorea, motor disability and neuropsychiatry features. The characterization of a good animal model is required to compare and contrast specific features with the human disease, in order to gain new insights on the consequences of chronic iron overload on brain function and behavior. To this aim we studied an animal model expressing the pathogenic human FTL mutant 498InsTC under the phosphoglycerate kinase (PGK) promoter. Transgenic (Tg) mice showed strong accumulation of the mutated protein in the brain, which increased with age, and this was accompanied by brain accumulation of ferritin/iron bodies, the main pathologic hallmark of human neuroferritinopathy. Tg-mice were tested throughout development and aging at 2-, 8- and 18-months for motor coordination and balance (Beam Walking and Footprint tests). The Tg-mice showed a significant decrease in motor coordination at 8 and 18 months of age, with a shorter latency to fall and abnormal gait. Furthermore, one group of aged naïve subjects was challenged with two herbicides (Paraquat and Maneb) known to cause oxidative damage. The treatment led to a paradoxical increase in behavioral activation in the transgenic mice, suggestive of altered functioning of the dopaminergic system. Overall, data indicate that mice carrying the pathogenic FTL498InsTC mutation show motor deficits with a developmental profile suggestive of a progressive pathology, as in the human disease. These mice could be a powerful tool to study the neurodegenerative mechanisms leading to the disease and help developing specific therapeutic targets.
authors.affiliation: Department of Cell Biology, Section of Behavioral Neuroscience, Istituto Superiore Di Sanità, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Capoccia
authors.affiliation: Department of Molecular and Translational Medicine, Section of Biotechnologies, University of Brescia, Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Maccarinelli
authors.affiliation: Department of Clinical and Experimental Sciences, Section of Anatomy and Physiopathology, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Buffoli
authors.affiliation: Department of Clinical and Experimental Sciences, Section of Anatomy and Physiopathology, University of Brescia, Brescia, Italy.
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Rodella
authors.affiliation: Università Vita-Salute San Raffaele & Centro di Imaging Sperimentale, Istituto Scientifico San Raffaele, Milano, Italy.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Cremona
authors.affiliation: Department of Molecular and Translational Medicine, Section of Biotechnologies, University of Brescia, Brescia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Cell Biology, Section of Behavioral Neuroscience, Istituto Superiore Di Sanità, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cirulli
mesh_terms: D000818:Animals; D001052:Apoferritins / Q000235:genetics; D001522:Behavior, Animal; D004195:Disease Models, Animal; D006801:Humans; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010735:Phosphoglycerate Kinase / Q000235:genetics; D004856:Postural Balance; D011401:Promoter Regions, Genetic; D011597:Psychomotor Performance
chemical_list: C507433:FTL protein, human; D001052:Apoferritins; D010735:Phosphoglycerate Kinase