| Abstract No.: | B-C2088 |
| Country: | USA |
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| Title: | DISRUPTION OF IRON HOMEOSTASIS IN THE SPINAL CORDS CAUSES NEURODEGENERATION IN MICE |
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| Authors/Affiliations: | 1 Suh Young Jeong*; 2 Bernard S. Jortner; 1 Hayden Ollivierre; 1 Manik Ghosh; 1 Sharon Cooperman; 1 Tracey A. Rouault;
1 MMP, NICHD, National Institute of Health, Bethesda, USA; 2 Verginia Tech, Blacksburg, USA
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| Content: | Background: Iron is essential for maintenance of many cellular processes including mitochondrial respiration, and myelin and neurotransmitter synthesis in the central nervous system (CNS). Iron is also a redox-active metal that can generate toxic free radicals if it is not properly regulated. In mammalian cells, regulation of expression of proteins involved in iron homeostasis is achieved by iron-sensing proteins called iron regulatory proteins (IRPs). There are two IRPs (IRP1 and IRP2) and we have previously reported that mice lacking IRP2 (IRP2-/-) show disruption of iron homeostasis in the brain. These mice develop a movement disorder accompanied with neuronal ferric iron accumulation and degeneration. We have also reported that double transgenic mice that lack one copy of IRP1 and both copies of IRP2 (IRP1+/-;IRP2-/-) show similar but faster progression of disease compared to IRP2-/-, therefore confirming a dose-dependent effect of the null mutations.
Objective: To study neurodegeneration in the spinal cords of IRP transgenic mice. Materials and Methods: 10 months old IRP2-/- and IRP1+/-;IRP2-/- mice spinal cords were analyzed and compared to age-matched control mice. Light microscopic analyses included Toluidine Blue and Luxol Fast Blue staining. Monoclonal anti-neurofilament antibody (SMI-32) and rabbit anti-ubiquitin antibodies were used for double-immunofluorescence staining. Results: Here we report that disruption of iron homeostasis in the spinal cords of IRP deletion mice caused significant degeneration of myelinated nerve fibers. Light microscopic analysis of spinal cords showed numerous myelin-dense bodies in the transgenic mice suggesting degeneration of myelinated fibers. Myelin-dense body accumulation was much higher in the double transgenic mice (65-fold increase to control), but were also significantly increased in the IRP2-/- mice (24-fold). Staining for stressed axons using SMI32 antibody was also increased in the transgenic animals, some of which are also positive for ubiquitin. Moreover, EM analysis showed axonal swelling with degeneration of cytoskeleton and aggregation of neurofilaments. Occasional demyelination was also detected using Luxol Fast Blue staining in the ventral white matter. Conclusion: These data demonstrate that disrupted iron homeostasis in the spinal cords of IRP transgenic mice leads to neurodegeneration. Currently how neuronal cell bodies regulate iron homeostasis along their axons is not known, but many common neurodegenerative disorders in human patients also suggest disruptions in iron homeostasis. Therefore, understanding IRPs in the CNS will help us explore these diseases in the future. |
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