#Ftl mouse acceleration free

Neuropathologically, the disease is characterized by the presence of ferritin nuclear (NI) and cytoplasmic inclusion bodies and iron accumulation in glia and neurons throughout the CNS. Magnetic resonance imaging (MRI) studies show cerebral and cerebellar atrophy and abnormal signals in the basal ganglia. The disease progresses gradually, affecting first striatal and cerebellar function, then later cortical functions. Clinically, HF is characterized by the presence of tremor, cerebellar ataxia, parkinsonism, pyramidal signs, behavioral disturbances, and cognitive decline the age at onset is in the third decade of life. We described a two-nucleotide (thymidine and cytidine) insertion at position 498–499 of the FTL gene ( FTL498–499InsTC) in members of a French kindred ( Vidal et al., 2004a) and documented for the first time that pathologic alterations extended beyond the CNS, suggesting the term “hereditary ferritinopathy” (HF) ( Vidal et al., 2003).

Recently, nucleotide insertions in the coding sequence of the ferritin light polypeptide ( FTL) gene have been found associated with the development of a novel autosomal dominant neurodegenerative disease ( Curtis et al., 2001 Vidal et al., 2004a Mancuso et al., 2005) or neuroferritinopathy ( Curtis et al., 2001). For that reason, the iron storage protein ferritin plays a key role to reduce the bio-availability of iron to stem uncontrolled production of reactive oxygen radicals that may result in cell death ( Harrison and Arosio, 1996).

#Ftl mouse acceleration free

Because of its ability to participate directly as a donor or acceptor in electron-transfer reactions, iron may become toxic by the generation of highly reactive free radicals that cause lipid peroxidation, DNA strand breaks, and protein modifications. Iron is an essential element needed for vital processes such as neuronal development, myelination, synthesis and catabolism of neurotransmitters, electron transport, and iron–sulfur cluster synthesis ( Beard and Connor, 2003). The FTH1 subunit has a potent ferroxidase activity that catalyzes the oxidation of ferrous iron, whereas the FTL subunit plays a role in iron nucleation and protein stability, giving ferritin the dual functions of iron detoxification and iron reserve. Mammalian ferritins are heteropolymers composed of 24 polypeptide subunits that contain variable proportions of the light (FTL) and heavy (FTH1) polypeptide subunits ( Harrison and Arosio, 1996). This new transgenic mouse represents a relevant model of HF in which to study the pathways that lead to neurodegeneration in HF, to evaluate the role of iron mismanagement in neurodegenerative disorders, and to evaluate potential therapies for HF and related neurodegenerative diseases. Expression of the transgene in mice leads to a significant decrease in motor performance and a shorter life span, formation of ferritin inclusion bodies, misregulation of iron metabolism, accumulation of ubiquitinated proteins, and incorporation of elements of the proteasome into inclusions. Our studies show histological, immunohistochemical, and biochemical similarities between ferritin inclusion bodies found in transgenic mice and in individuals with HF. As in HF, ferritin inclusions are seen in glia and neurons throughout the CNS as well as in cells of other organ systems.

Here we report that the expression in transgenic mice of a human FTL cDNA carrying a thymidine and cytidine insertion at position 498 ( FTL498–499InsTC) leads to the formation of nuclear and cytoplasmic ferritin inclusion bodies. HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic ferritin inclusion bodies in glia and neurons throughout the CNS and in tissues of multiple organ systems. The finding that mutations in the ferritin light polypeptide ( FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy (HF) provided a direct connection between abnormal brain iron storage and neurodegeneration. Increased iron levels and iron-mediated oxidative stress play an important role in the pathogenesis of many neurodegenerative diseases.