title: Possible involvement of iron-induced oxidative insults in neurodegeneration.
abstract: Involvement of iron in the development of neurodegenerative disorders has long been suggested, and iron that cannot be stored properly is suggested to induce iron toxicity. To enhance iron uptake and suppress iron storage in neurons, we generated transgenic (Tg) mice expressing iron regulatory protein 2 (IRP2), a major regulator of iron metabolism, in a neuron-specific manner. Although very subtle, IRP2 was expressed in all regions of brain examined. In the Tg mice, mitochondrial oxidative insults were observed including generation of 4-hydroxynonenal modified proteins, which appeared to be removed by a mitochondrial quality control protein Parkin. Inter-crossing of the Tg mice to Parkin knockout mice perturbed the integrity of neurons in the substantia nigra and provoked motor symptoms. These results suggest that a subtle, but chronic increase in IRP2 induces mitochondrial oxidative insults and accelerates neurodegeneration in a mouse model of Parkinson's disease. Thus, the IRP2 Tg may be a useful tool to probe the roles of iron-induced mitochondrial damages in neurodegeraration research.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Asano
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Sakata
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Department of Neurology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Hatano
authors.affiliation: Department of Neurology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohashi
authors.affiliation: Research Institute for Diseases of Old Age, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Funayama
authors.affiliation: Department of Neurophysiology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshimi
authors.affiliation: Department of Brain Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Asanuma
authors.affiliation: Department of Pathology and Biological Responses, Graduate School of Medicine, Nagoya University, Nagoya, Aichi 466-8550, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Toyokuni
authors.affiliation: Department of Neurology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Neurology, Juntendo University, School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: nhattori@juntendo.ac.jp.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Medicine and Cell Biology and Metabolism Group, Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: kiwai@mcp.med.kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003433:Crosses, Genetic; D059290:Dopaminergic Neurons / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009043:Motor Activity; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D007501:Iron; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D035942:Iron Regulatory Protein 2
keywords: Iron; Iron regulatory protein; Mitochondria; Oxidative stress; Parkin; Parkinson’s disease