Behavioral Characterization of Mouse Models of Neuroferritinopathy

Autor: Ottavio Cremona, Sara Capoccia, Francesca Cirulli, Luigi Fabrizio Rodella, Federica Maccarinelli, Paolo Arosio, Barbara Buffoli
Přispěvatelé: Capoccia, S, Maccarinelli, F, Buffoli, B, Rodella, Lf, Cremona, Ottavio, Arosio, P, Cirulli, F.
Rok vydání: 2015
Předmět:
Genetically modified mouse
Pathology
medicine.medical_specialty
Cerebellum
Neuroaxonal Dystrophies
lcsh:Medicine
Neuroferritinopathy
Mice
Transgenic
Biology
Mice
Internal medicine
Basal ganglia
medicine
Animals
Humans
lcsh:Science
Promoter Regions
Genetic
Postural Balance
Neuroferritinopathy SB - IM MH - Animals MH - Apoferritins/genetics MH - *Behavior
Animal MH - Disease Models
Animal MH - Humans MH - *Iron Metabolism Disorders/genetics/metabolism/physiopathology MH - Mice MH - Mice
Transgenic MH - Mutation MH - *Neuroaxonal Dystrophies/genetics/metabolism/physiopathology MH - Phosphoglycerate Kinase/genetics MH - Postural Balance MH - Promoter Regions
Genetic MH - Psychomotor Performance
Dystonia
Multidisciplinary
Behavior
Animal
lcsh:R
medicine.disease
Iron Metabolism Disorders
Motor coordination
Ferritin light chain
Ferritin
Disease Models
Animal
Phosphoglycerate Kinase
medicine.anatomical_structure
Endocrinology
Apoferritins
Mutation
biology.protein
lcsh:Q
Psychomotor Performance
Research Article
Zdroj: PLoS ONE
PLoS ONE, Vol 10, Iss 2, p e0118990 (2015)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0118990
Popis: 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.
Databáze: OpenAIRE
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