Molecular characterization and gene/regeneration therapy for amyotrophic lateral sclerosis

2008 Fiscal Year Final Research Report

• Project/Area Number: 18390257
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Okayama University
• Principal Investigator: ABE Koji Okayama University, 大学院・医歯薬学総合研究科, 教授 (20212540)
• Co-Investigator(Kenkyū-buntansha): KAMIYA Tatsushi 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (70233955) ; IKEDA Yoshio 岡山大学, 医学部・歯学部附属病院, 講師 (00282400) ; TAKEHISA Yasushi 岡山大学, 医学部・歯学部附属病院, 助教 (00379752) ; NAGAI Makiko 岡山大学, 医学部・歯学部附属病院, 助教 (80420488) ; MURAKAMI Tetsuro 岡山大学, 医学部・歯学部附属病院, 助教 (70403475)
• Project Period (FY): 2006 – 2008
• Keywords: 神経分子病態学 / 筋萎縮性側索硬化症 / ALS / SOD1 / トランスジェニックマウス / 蛋白療法 / 遺伝子療法 / 再生療法

Research Abstract

筋萎縮性側索硬化症(ALS)の病態を明らかにし、早期に有効な治療法を開発するため、ALSモデルマウスを用いてALS病態に関連する種々の分子の役割を明らかにした.また、ALS患者の脳脊髄液中に早期の確定診断を得るためのマーカーとなり得る分子があるかどうかを検討し、その候補を得た.また、再生療法と関連して、脊髄における内在性神経幹細胞の動態と各種神経栄養因子の神経幹細胞に対する活性化作用を明らかにした.さらにALSモデルマウスに対して、TAT融合蛋白の髄腔内持続投与による蛋白療法を開発し、良好な治療効果を得た.本研究による成果はALS患者の新規治療法の開発と臨床応用へ向けて、重要な知見を与えるものと考えられる.

Research Products

• [Journal Article] Progressive decrease in the level of YAPdeltaCs, prosurvival isoforms of YAP, in the spinal cord of transgenic mouse carrying a mutant SOD1 gene (2009)
  • Author(s): Morimoto N, Nagai M, Miyazaki K, Kurata T, Takehisa Y, Ikeda Y, Kamiya T, Okazawa H, Abe K.
  • Journal Title: J Neurosci Res 87 Pages: 928-936
  • Peer Reviewed
• [Journal Article] Therapeutic Strategy for Ischemic Stroke (2009)
  • Author(s): Yamashita T, Deguchi K, Sehara Y, Lukic-Panin V, Zhang H, Kamiya T, Abe K.
  • Journal Title: Neurochem Res 34 Pages: 707-710
  • Peer Reviewed
• [Journal Article] Motor impairment ameliorated by L-DOPA administration in human alpha-synuclein A30P+A53T transgenic mice with alpha-synuclein pathology (2009)
  • Author(s): Ikeda M, Kawarabayashi T, Harigaya Y, Sasaki A, Yamada S, Matsubara E, Murakami T, Tanaka Y, Kurata T, Wuhua X, Ueda K, Kuribara H, Ikarashi Y, Nakazato Y, Okamoto K, Abe K, Shoji M.
  • Journal Title: Brain Res 1250 Pages: 232-241
  • Peer Reviewed
• [Journal Article] Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis (2008)
  • Author(s): Ohta Y, Kamiya T, Nagai M, Nagata T, Morimoto N, Miyazaki K, Murakami T, Kurata T, Takehisa Y, Ikeda Y, Asoh S, Ohta S, Abe K.
  • Journal Title: J Neurosci Res 86 Pages: 3028-3037
  • Peer Reviewed
• [Journal Article] Sendai virus-mediated gene transfer of GDNF reduces AIF translocation and ameliorates ischemic cerebral injury (2008)
  • Author(s): Jin G, Inoue M, Hayashi T, Deguchi K, Nagotani S, Zhang H, Wang X, Shoji M, Hasegawa M, Abe K.
  • Journal Title: Neurol Res 30 Pages: 731-739
  • Peer Reviewed
• [Journal Article] (2008)
  • Author(s): Kurata T, Hayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Kawarabayashi T, Takao Y, Ohta T, Harigaya Y, Manabe Y, Kamiya T, Shoji M, Abe K.
  • Journal Title: Neurol Res 30 Pages: 860-867
  • Peer Reviewed
• [Journal Article] Reduction of cerebrainfarction in rats by biliverdin associated with amelioration of oxidative stress (2008)
  • Author(s): Deguchi K, Hayashi T, Nagotani S, Sehara Y, Zhang H, Tsuchiya A, Ohta Y, Tomiyama K,Morimoto N, Miyazaki M, Huh NH, Nakao A, Kamiya T, Abe K.
  • Journal Title: Brain Res 1188 Pages: 1-8
  • Peer Reviewed
• [Journal Article] Gelatin-siloxane hybrid scaffolds with vascular endothelial growth factor induces brain tissue regeneration (2008)
  • Author(s): Zhang H, Kamiya T, Hayashi T, Tsuru K, Deguchi K, Lukic V, Tsuchiya A, Yamashita T, Hayakawa S, Ikeda Y, Osaka A, Abe K.
  • Journal Title: Curr Neurovasc Res 5 Pages: 112-117
  • Peer Reviewed
• [Journal Article] Plasma antibodies to Abeta40 and Abeta42 in patients with Alzheimer's disease and normal controls (2008)
  • Author(s): Xu W, Kawarabayashi T, Matsubara E, Deguchi K, Murakami T, Harigaya Y, Ikeda M, Amari M, Kuwano R, Abe K, Shoji M.
  • Journal Title: Brain Res 1219 Pages: 169-179
  • Peer Reviewed
• [Journal Article] Increased autophagy in transgenic mice with a G93A mutant SOD1 gene (2007)
  • Author(s): Morimoto N, Nagai M, Ohta Y, Miyazaki K, Kurata T, Morimoto M, Murakami T, Takehisa Y, Ikeda Y, Kamiya T, Abe K.
  • Journal Title: Brain Res 1167 Pages: 112-117
  • Peer Reviewed
• [Journal Article] Early decrease of mitochondrial DNA repair enzymes in spinal motor neurons of presymptomatic transgenic mice carrying a mutant SOD1 gene (2007)
  • Author(s): Murakami T, Nagai M, Miyazaki K, Morimoto N, Ohta Y, Kurata T, Takehisa Y, Kamiya T, Abe K.
  • Journal Title: Brain Res 1150 Pages: 182-189
  • Peer Reviewed
• [Journal Article] Increased ER stress during motor neuron degeneration in a transgenic mouse model of amyotrophic lateral sclerosis (2007)
  • Author(s): Nagata T, Ilieva H, Murakami T, Shiote M, Narai H, Ohta Y, Hayashi T, Shoji M, Abe K.
  • Journal Title: Neurol Res 29 Pages: 767-771
  • Peer Reviewed
• [Journal Article] Abe KElevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients (2007)
  • Author(s): Nagata T, Nagano I, Shiote M, Narai H, Murakami T, Hayashi T, Shoji M
  • Journal Title: Neurol Res 29 Pages: 772-776
  • Peer Reviewed
• [Journal Article] Enhanced accumulation ophosphorylated alpha-synuclein in double transgenic mice expressing mutant beta-amyloid precursor protein and presenilin-1 (2007)
  • Author(s): Kurata T, Kawarabayashi T, Murakami T, Miyazaki K, Morimoto N, Ohta Y, Takehisa Y, Nagai M, Ikeda M, Matsubara E, Westaway D, Hyslop PS, Harigaya Y, Kamiya T, Shoji M, Abe K.
  • Journal Title: J Neurosci Res 85 Pages: 2246-2252
  • Peer Reviewed
• [Journal Article] Two cases of spinocerebellar ataxiaccompanied by involvement of the skeletal motor neuron system and bulbar palsy (2007)
  • Author(s): Ohta Y, Hayashi T, Nagai M, Okamoto M, Nagotani S, Nagano I, Ohmori N, TakehisaY, Murakami T, Shoji M, Kamiya T, and Abe K.
  • Journal Title: Intern Med 46 Pages: 751-755
  • Peer Reviewed
• [Journal Article] Intrathecal injection of epidermal growth factor and fibroblast growth factor 2 promotes proliferation of neural precursor cells in the spinal cords of mice with mutant human SOD1 gene (2006)
  • Author(s): Ohta Y, Nagai M, Nagata T, Murakami T, Nagano I, Narai H, Kurata T, Shiote M, Shoji M, Abe K.
  • Journal Title: J Neurosci Res 84 Pages: 980-992
  • Peer Reviewed
• [Journal Article] Implantation of a new porous gelatin-siloxane hybrid into a brain lesion as a potential scaffold for tissue regeneration (2006)
  • Author(s): Deguchi K, Tsuru K, Hayashi T, Takaishi M, Nagahara M, Nagotani S, Sehara Y, Jin G, Zhang H, Hayakawa S, Shoji M, Miyazaki M, Osaka A, Huh NH, Abe K.
  • Journal Title: J Cereb Blood Flow Metab 26 Pages: 1263-1273
  • Peer Reviewed
• [Journal Article] Parvalbumin and calbindin D-28k immunoreactivity in transgenic mice with a G93A mutant SOD1 gene (2006)
  • Author(s): Sasaki S, Warita H, Komori T, Murakami T, Abe K, Iwata M.
  • Journal Title: Brain Res 1083 Pages: 196-203
  • Peer Reviewed
• [Journal Article] Distribution of inducible nitric oxide synthase and cell proliferation in rat brain after transientmiddle cerebral artery occlusion (2006)
  • Author(s): Sehara Y, Hayashi T, Deguchi K, Nagotani S,Zhang H,Shoji M, Abe K.
  • Journal Title: Res 1093 Pages: 190-197
  • Peer Reviewed
• [Journal Article] Subventricular zone-derived neuroblasts migrate and differentiate intomature neurons in the post-stroke adult striatum (2006)
  • Author(s): Yamashita T, Ninomiya M, Hernandez AcosP, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T, Hirota Y, Kawase T, Araki N, Abe K, Okano H, K.
  • Journal Title: J Neurosci 26 Pages: 6627-6636
  • Peer Reviewed
• [Journal Article] Cortical neuronal and glial pathology TgTauP301L transgenic mice : neuronal degeneration, memory disturbance, and phenotypic variation (2006)
  • Author(s): Murakami T, Paitel E, Kawarabayashi T, Ikeda M, Chishti MA, Janus C, Matsubara E, Sasaki A, Kawarai T, Phinney AL, Harigaya Y, Horne P, Egashira N, Mishima K, Hanna A, Yang J, Iwasaki K, Takahashi M, Fujiwara M, Ishiguro K, Bergeron C, Carlson GA, Abe K, Westaway D, St George-Hyslop P, Shoji M.
  • Journal Title: Am J Pathol 169 Pages: 1365-1375
  • Peer Reviewed
• [Presentation] Disruption of microvascintegrity after thrombolysis and reperfusion in ischemic rat brain (2008)
  • Author(s): Yamashita T, Kamiya T, Deguchi K, Inaba T,Zhang H, Miyazaki K, Ohtsuka A, Katayama Yand Abe K.
  • Organizer: The 4nd Korean-Japanese Joint Stroke Conference
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 20081121-23
• [Presentation] A free radical scavenger Edaravone improves the motor acute lacunar infarction (2008)
  • Author(s): Takamiya M, Takeda I, Ohta Y, Matsushima H, Fukushima T, Ota T, Takamatsu K, Goto K, and Abe K.
  • Organizer: The 4nd Korean-Japanese Joint Stroke Conference
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 20081121-23
• [Presentation] Dissociation of neurovascular unit after thrombolysis and reperfusionischemic rat brain (2008)
  • Author(s): Yamashita T, Kamiya T, Deguchi K, Inaba T, Zhang H, Miyazaki K, Ohtsuka A, Katayama Y, and Abe K.
  • Organizer: 6th World Stroke Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-27
• [Presentation] A Rho-kinase inhibitor prevents apoptosis-induced neuronal cell death following transient focal ischemia in rats (2008)
  • Author(s): Kamiya T, Inaba T, Nito C, Ueda M, Kato K, Suda S, Hayashi T, Deguchi K, Yamashita T, Sehara Y, Tsuchiya A, Han Zhe Zhang, V, Katayama Y, Abe K.
  • Organizer: 6th World Stroke Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-27
• [Presentation] Reduction of cerebral infarction in rats by biliverdin associated with amelioration of oxidstress (2008)
  • Author(s): Deguchi K, Hayashi T, Nagotani S, Sehara Y, HanZhe Zhang, Tsuchiya A, Ohta Y, TomiyamK, Morimoto N, Miyazaki M, Nam-ho Huh, Nakao A, Kamiya T, Abe K.
  • Organizer: 6th World Stroke Congre
  • Place of Presentation: Vienna, Austria
  • Year and Date: 20080924-27
• [Presentation] Increased autophagy in transgenic mice with a G93A mutant SOD1 gene (2008)
  • Author(s): Morimoto N, Nagai M, Miyazaki K, KurataT, Takehisa Y, Ikeda Y, Kamiya T, Abe K.
  • Organizer: 12th Congress of the European Federation of Neurologica Societies
  • Place of Presentation: Madrid, Spain
  • Year and Date: 20080823-26
• [Presentation] Preventionof neuronal damage by calcium channel blockers with antioxidative effects aftertransient focal ischemia in rats (2008)
  • Author(s): Violeta Lukic-Panin, Kamiya T, HanZhe Zhang, Hayashi T, Tsuchiya A, Sehara Y, Deguchi K, Yamashita T, Abe K.
  • Organizer: 5th International Conference on Neuroprotection and Neurorepair, CerIschemia and Stroke
  • Place of Presentation: Magdeburg, Germany
  • Year and Date: 20080517-20
• [Presentation] Intrathecal injection of EGF and FGF2 promotes proliferation of neural precursor cells in the spinal cords owith mutant human SOD1 gene (2007)
  • Author(s): Ohta Y, Nagai M, Nagata T, Murakami T, Nagano I, Narai H, Kurata T, Shiote M, Shoji M, and Abe K.
  • Organizer: 12thInternational Congress of World Muscle Society
  • Place of Presentation: Naxos, Italy
  • Year and Date: 20071017-20
• [Presentation] Enhanced accumulation of phosphorylated α-synuclein in transgenic mice eAPP and PS-1 (2007)
  • Author(s): Kurata T, Kawarabayashi T, Murakami T, Morimoto N, Ota Y, Ikeda Y, Nagai M, Takehisa Y, Matsubara E, David Westaway, Peter St. George Hyslop, Harigaya Y, T, Shoji M, and Abe K.
  • Organizer: 13th Congress of International Psychogeriatric
  • Place of Presentation: Osaka, Japan
  • Year and Date: 20071014-18
• [Presentation] Beneficial Effectsof Intrathecal Administration in Patientswith Amyotrophic Lateral Screlosis (2007)
  • Author(s): Morimoto N, Nagano I, Murakami T, Nagai M, Shiote M, Ohta Y, Morimoto M, Takehisa Y, Kamiya T, and Abe K.
  • Organizer: The 23rd International Symposium on CereBlood Flow, Metabolism and ThInternational Conference on Quantification of Brain Funct
  • Place of Presentation: Osaka, Japan
  • Year and Date: 20070521-24
• [Presentation] Therapeubenefit of intrathecal injection of insulin-like growth factor-1 in a mouse model of Amyotrophic Lateral Sclerosi (2007)
  • Author(s): Miyazaki K, Nagano I, Ilieva H, Murakami T, Yokoyama M, Shoji M, and Abe K.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, MetabolisInternational Conference on Quantification of Brain Funct
  • Place of Presentation: Osaka, Japan
  • Year and Date: 20070521-24
• [Presentation] Dysfunction ofmitochondrial oxidative phosphorylation in ALS rat model (2007)
  • Author(s): Nagai M, Murakami T, Ohta Y, Takehisa Y, Morimoto N, Miyazaki K, Kurata T, Kamiya T, Abe K, and Przedborski S.
  • Organizer: The 23rd InternatSymposium on Cerebral Blood Flow, Metabolism and The 8th International Conference on Quantification of Brain Functio with PET
  • Place of Presentation: Osaka, Japan
  • Year and Date: 20070521-24
• [Presentation] Familial ALS with a novel Leu126Ser mutation in the SOD1 gene showing mild clinical features and low penetrance in females (2007)
  • Author(s): Takehisa Y, Murakami T, Nagai M, Ohta Y, Morimoto N, Ikeda Y, Kamiya T, and Abe K.
  • Organizer: The 23rd International Symposium on Cerebral Blood Flow, Metabolism8th International Conference on Quantification of Brain Function with PET
  • Place of Presentation: Osaka, Japan
  • Year and Date: 20070521-24
• [Presentation] Beneficial effects of intrathecal IGF-1 administration inpatients with amyotrophic lateralsclerosis (2006)
  • Author(s): Murakami T, Nagano I, Nagai M, Shiote M, Ohta Y, Morimoto N, Takehisa Y, Kaand Abe K.
  • Organizer: 17^<th> International Symposium on ALS/MND
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 20061130-1202
• [Presentation] Accumulation of Parkinson's-disease-related moleculLewy bodies and glial cytoplasmic inclusions (2006)
  • Author(s): Murakami T, Imai Y, Inoue H, Kawarabayashi T, Nagai M, Kurata T, Takehisa Y, Harig Y, Shoji M, Takahashi Y, Harigaya Y, Shoji M, Takahashi R, and Abe K.
  • Organizer: 10^<th> International Congress of Parkinson's Disease and Movement
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20061028-1102
• [Presentation] Enhanced accumulation of phosphorylated α-synuclein in transgenic mice expressingAPP and PS-1 (2006)
  • Author(s): Kurata T, Kawarabayashi T, Murakami T, Miyazaki K, Morimoto N, Ota Y, Takehisa Y, Nagai M, Ikeda M, Matsubara E, Westaway D, St George Hyslop P, Harigaya Y, Kamiya T, Shoji M, and Abe K.
  • Organizer: The 6^<th> Annual Meetingof International Collegeof Geriatric Psychoneuropharmacology
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 20061003-06
• [Presentation] Subventricular Zone-Derived Neuroblasts Migrate and Differentiate into Mature Neurons in the Post-Stroke AdultStriatum (2006)
  • Author(s): Yamashita T, Sawamoto K, Okano H, Kamiya Tand Abe K.
  • Organizer: Gordon Research Conference : Brain Energy Metabolism & Blood
  • Place of Presentation: Oxford, England
  • Year and Date: 20060820-25
• [Presentation] Pael-R is accumulated in Lewy bodies of dementia with Lewy bodies and Parkinson's disease (2006)
  • Author(s): Murakami T, Kawarabayashi T, Kurata T, Inoue H, Moriwaki Y, Shoji M, Takahashi R, and Abe K.
  • Organizer: 10^<th> International conference on Alzheimer's disease and Rrelated disorders
  • Place of Presentation: Madrid, Spain
  • Year and Date: 20060715-20
• [Book] 神経難病のすべて~症状・診断から最先端治療、福祉の実際まで~ (2007)
  • Author(s): 阿部康二(編著)
  • Total Pages: 389
  • Publisher: 新興医学出版社
• [Remarks] 岡山大学神経内科
  • URL: http://www.okayama-u.ac.jp/user/med/shinkeinaika