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.
Highlights
Iron is essential for cell viability, including electron transport in the respiratory chain, catabolism of neurotransmitters and neuronal development and myelination in the central nervous system [1,2,3,4]
We studied a new transgenic mouse model, similar to that described by Vidal, expressing the same pathogenic mutant of human ferritin-L chain but under the phosphoglycerate kinase (PGK) promoter, that has recently been characterized [40]
Neuroferritinopathy is caused by 9 types of mutation in the FTL gene, the most common is the 460InsA, with more than 40 patients described [25]
Summary
Iron is essential for cell viability, including electron transport in the respiratory chain, catabolism of neurotransmitters and neuronal development and myelination in the central nervous system [1,2,3,4]. Brain iron levels are not detectable at birth and start accumulating later during development. High iron deposition occurs in most neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases, amyothropic lateral sclerosis, prion disease and a pool of genetic disorders collectively identified as Neurodegeneration with Brain Iron Accumulation (NBIA) [8, 9]. In these pathologies, local alterations of iron levels and/or of proteins involved in iron metabolism ( ferritins) have been reported, but it is unclear whether this is a causative factor or whether it represents a consequence of the degenerative processes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
