The analysis of participation in the ubiquitin proteasome system for understanding the mechanisms of neurodegenerative diseases.

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390244
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto University
• Principal Investigator: TAKAHASHI Ryosuke Kyoto University, 医学研究科, 教授 (90216771)
• Co-Investigator(Kenkyū-buntansha): INOUE Haruhisa 京都大学, 医学研究科, 助教 (70332327) ; KAWAMATA Jun 札幌医科大学, 医学部, 講師 (60360814) ; MISAWA Hidemi 慶応義塾大学, 薬学部, 教授 (80219617)
• Project Period (FY): 2008 – 2010
• Keywords: ALS / 運動ニューロン / プロテアソーム / Rpt3 / コンディショナルノックアウト

Research Abstract

We have established motor neuron-specific proteasome deficient mice by crossbreeding of flexed mice for Rpt3, a subunit of 26S proteasome with VAChT-Cre. Fast mice that displays motor neuron specific Cre expression. The motor neuron specific Rpt3 deficient mice showed tremor starting from 8 weeks of age and slowly progressive motor dysfunction from 12 weeks of age. Pathological findings revealed increased expression of the gene products of familial ALS such as FUS and TDP43, the latter forming cytoplasmic inclusion bodies. These results suggest that motor neuron-specific Rpt3 deficient mice represent a model for sporadic ALS.

Research Products

• [Journal Article] Chemical library screeningidentifies a small molecule that downregulates SOD1 transcription for drugs to treat ALS. (2011)
  • Author(s): Murakami G, Inoue H, Tsukita K, Asai Y, Amagai Y, Aiba K, Shimogawa H, Uesugi M, Nakatsuji N, Takahashi R
  • Journal Title: J Biomol Screen. (in press)
  • Peer Reviewed
• [Journal Article] The endoplasmic reticulum stress sensor, ATF6{alpha}, protects against neurotoxin-induced dopaminergic neuronal death. (2011)
  • Author(s): Egawa N, Yamamoto K, Inoue H, Hikawa R, Nishi K, Mori K,Takahashi R.
  • Journal Title: J Biol Chem. 286 Pages: 7947-7957
  • Peer Reviewed
• [Journal Article] N-cadherin regulates p38MAPK signaling via association with JLP:Implications for neurodegeneration in Alzheimer's disease. (2011)
  • Author(s): Ando K, Uemura K, Kuzuy A, Kubota M, Maesako M, Asada M, Takahashi R, Kinoshita A
  • Journal Title: J Biol Chem. 286 Pages: 7619-7628
  • Peer Reviewed
• [Journal Article] The loss of PGAM5 suppresses the mitochondrial degeneration caused by inactivation of PINK1 in Drosophila. (2010)
  • Author(s): Imai Y, Kanao T, SawadaT, Kobayashi Y, Moriwaki Y, Ishida Y, Takeda K, Ichijo H, Lu B, Takahashi R.
  • Journal Title: Plos Genetics. Epub Dec2;6(12)
  • Peer Reviewed
• [Journal Article] Ammonium chloride and tunicamycin are novel toxins for dopaminergic neurons and induced Parkinson's disease-like phenotypes in medaka fish. (2010)
  • Author(s): Matsui H, Ito H, Taniguchi Y, Takeda S, Takahashi R.
  • Journal Title: J Neurochem. 115 Pages: 1150-1160
  • Peer Reviewed
• [Journal Article] Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. (2010)
  • Author(s): Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S.
  • Journal Title: J Neurosci. 30 Pages: 11917-11925
  • Peer Reviewed
• [Journal Article] Proteasome inhibition in medaka brain induces the features of Parkinson disease. (2010)
  • Author(s): Matsui H, Ito H, Inoue H, Taniguchi Y, Takeda S, Takahashi R.
  • Journal Title: J Neurochem. 115 Pages: 178-187
  • Peer Reviewed
• [Journal Article] Nonhypotensive Dose of Telmisartan Attenuates Cognitive Impairment Partially due to Peroxisome Proliferator-Activated Receptor-γ Activation in Mice with Chronic Cerebral Hypoperfusion. (2010)
  • Author(s): Washida K, Ihara M, Nishio K, Fujita Y, Maki T, Yamada M, Takahashi J, Wu X, Kihara T, Ito H, Tomimoto H, Takahashi R.
  • Journal Title: Stroke 41 Pages: 1798-1806
  • Peer Reviewed
• [Journal Article] HtrA2/Omi-immunoreactive intraneuronal inclusions in the anterior horn from patients with sporadic and SOD1 mutant amyotrophic lateral sclerosis. (2010)
  • Author(s): Kawamoto Y, Ito H, Kobayashi Y, Suzuki Y, Ihara M, Kawamata J, Akiguchi I, Fujimura H, Sakoda S, Kusaka H, Hirano A, Takahashi R
  • Journal Title: Neuropath. Appl.Neurobiol. 36 Pages: 331-344
  • Peer Reviewed
• [Journal Article] PI3K inhibition causes the accumulation of ubiquitinated presenilin 1 without affecting the proteasome activity. (2010)
  • Author(s): Aoyagi N, Uemura K, Kuzuya A, Kihara T, Kawamata J, Shimohama S, Kinoshita A, Takahashi R
  • Journal Title: Biochem. Biophys. Res.Commun. 391 Pages: 1240-1245
  • Peer Reviewed
• [Journal Article] Loss of PINK1 in medaka fish (Oryzias latipes) causes late-onset decrease in spontaneous movement. (2010)
  • Author(s): Matsui H, Taniguchi Y, Inoue H, Kobayashi Y, Sakaki Y, Toyoda A, Uemura K, Kobayashi D, Takeda S, Takahashi R
  • Journal Title: Neurosci Res. 66 Pages: 151-161
  • Peer Reviewed
• [Journal Article] Dopamine facilitates alpha-synuclein oligomerization in human neuroblastoma SH-SY5Y cells. (2009)
  • Author(s): Yamakawa K, Izumi Y, Takeuchi H, Yamamoto N, Kume T, Akaike A, Takahashi R, Shimohama S, Sawada H.
  • Journal Title: Biochem Biophys Res Commun. Nov11 [Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Selective nuclear shrinkage of oligodendrocytes lacking glial cytoplasmic inclusions in multiple system atrophy : a3-dimensional volumetric study. (2009)
  • Author(s): Uyama N, Uchihara T, Mochizuki Y, Nakamura A, Takahashi R, Mizutani T.
  • Journal Title: J Neuropathol Exp Neurol. 68 Pages: 1084-1091
  • Peer Reviewed
• [Journal Article] Abnormal auditory cortex with giant N100m signal in patients with autosomal dominant lateral temporal lobe epilepsy. (2009)
  • Author(s): Usui K, Ikeda A, Nagamine T, Matsubayashi J, Matsumoto R, Hiraumi H, Kawamata J, Matsuhashi M, Takahashi R, Fukuyama H.
  • Journal Title: Clin Neurophysiol. 120 Pages: 1923-1926
  • Peer Reviewed
• [Journal Article] Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy : The first report from Asian families. (2009)
  • Author(s): Kawamata J, Ikeda A, Fujita Y, Usui K, Shimohama S, Takahashi R
  • Journal Title: Epilepsia. Sep22.[Epub ahead of print]
  • Peer Reviewed
• [Journal Article] A chemical neurotoxin, MPTP induces Parkinson's disease like phenotype, movement disorders and persistent loss of dopamine neurons in medaka fish. (2009)
  • Author(s): Matsui H, Taniguchi Y, Inoue H, Uemura K, Takeda S, Takahashi R
  • Journal Title: Neurosci Res. 65 Pages: 263-271
  • Peer Reviewed
• [Journal Article] Leukoencephalopathy with cognitive impairment following tocilizumab for the treatment of rheumatoid arthritis (RA). (2009)
  • Author(s): Kobayashi K, Okamoto Y, Inoue H, Usui T, Ihara M, Kawamata J, Miki Y, Mimori T, Tomimoto H, Takahashi R
  • Journal Title: Intern Med. 48 Pages: 1307-1309
  • Peer Reviewed
• [Journal Article] Chronic cerebral hypoperfusion accelerates amyloid beta deposition in APPSwInd transgenic mice. (2009)
  • Author(s): Kitaguchi H, Tomimoto H, Ihara M, Shibata M, Uemura K, Kalaria RN, Kihara T, Asada-Utsugi M, Kinoshita A, Takahashi R
  • Journal Title: Brain Res. 1294 Pages: 202-210
  • Peer Reviewed
• [Journal Article] Attenuation of proteolysis-mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers. (2009)
  • Author(s): Ikeuchi K, Marusawa H, Fujiwara M, Matsumoto Y, Endo Y, Watanabe T, Iwai A, Sakai Y, Takahashi R, Chiba T
  • Journal Title: Int J Cancer. 125 Pages: 2029-2035
  • Peer Reviewed
• [Journal Article] Cortical microinfarcts in Alzheimer's disease and subcortical vascular dementia. (2009)
  • Author(s): Okamoto Y, Ihara M, Fujita Y, Ito H, Takahashi R, Tomimoto H
  • Journal Title: Neuroreport. 20 Pages: 990-996
  • Peer Reviewed
• [Journal Article] Negative motor seizure arising from the negative motor area : is it ictal apraxia? (2009)
  • Author(s): Ikeda A, Hirasawa K, Kinoshita M, Hitomi T, Matsumoto R, Mitsueda T, Taki JY, Inouch M, Mikuni N, Hori T, Fukuyama H, Hashimoto N, Shibasaki H, Takahashi R
  • Journal Title: Epilepsia. 50 Pages: 2072-2084
  • Peer Reviewed
• [Journal Article] Diagnostic accuracy of cardiac metaiodobenzylguanidine scintigraphy in Parkinson disease. (2009)
  • Author(s): Sawada H, Oeda T, Yamamoto K, Kitagawa N, Mizuta E, Hosokawa R, Ohba M, Nishio R, Yamakawa K, Takeuchi H, Shimohama S, Takahashi R, Kawamura T
  • Journal Title: Eur J Neurol. 16 Pages: 174-182
  • Peer Reviewed
• [Journal Article] Autoimmune autonomic ganglionopathy with Sjogren's syndrome : significance of ganglionic acetylcholine receptor antibody and th erapeutic approach. (2009)
  • Author(s): Kondo T, Inoue H, Usui T, Mimori T, Tomimoto H, Vernino S, Takahashi R
  • Journal Title: Auton Neurosci. 146 Pages: 33-35
  • Peer Reviewed
• [Journal Article] N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio. (2009)
  • Author(s): Uemura K, Lill CM, Banks M, Asada M, Aoyagi N, Ando K, Kubota M, Kihara T, Nishimoto T, Sugimoto H, Takahashi R, Hyman BT, Shimohama S, Berezovska O, Kinoshita A.
  • Journal Title: J.Neurochem. 108 Pages: 350-360
  • Peer Reviewed
• [Journal Article] Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models. (2009)
  • Author(s): Takeuchi H, Yanagida T, Inden M, Takata K, Kitamura Y, Yamakawa K, Sawada H, Izumi Y, Yamamoto N, Kihara T, Uemura K, Inoue H, Taniguchi T, Akaike A, Takahashi R, Shimohama S
  • Journal Title: J Neurosci Res. 87 Pages: 576-585
  • Peer Reviewed
• [Journal Article] Edaravone in ALS. (commentary) (2009)
  • Author(s): Takahashi R
  • Journal Title: Exp Neurol. 217 Pages: 235-236
  • Peer Reviewed
• [Journal Article] Accumulation of HtrA2/Omi in neuronal and glial inclusions in brains withalphasynucleinopathies. (2008)
  • Author(s): Kawamoto Y, Kobayashi Y, Suzuki Y, Inoue H, Tomimoto H, Akiguchi I, Budka H, Martins LM, Downward J, Takahashi R
  • Journal Title: J.Neuropathol Exp Neurol. 67 Pages: 984-993
  • Peer Reviewed
• [Journal Article] Parkin as a tumor suppressor gene for hepatocellular carcinoma. (2008)
  • Author(s): Fujiwara M, Marusawa, H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T
  • Journal Title: Oncogene. 27 Pages: 6002-6011
  • Peer Reviewed
• [Journal Article] Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. (2008)
  • Author(s): Wang HQ, Imai Y, Inoue H, Kataoka A, Iita S, Nukina N, Takahashi R
  • Journal Title: J.Neurochem. 107 Pages: 171-185
  • Peer Reviewed
• [Journal Article] Phosphorylation of 4E-BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila. (2008)
  • Author(s): Imai Y, Gehrke S, Wang HQ, Takahashi R, Hasegawa K, Oota E, Lu B
  • Journal Title: EMBO J. 27 Pages: 2432-2443
  • Peer Reviewed
• [Journal Article] Rines/RNF180, a novel RING finger gene-encoded product, is a membrane-bound ubiquitin ligase. (2008)
  • Author(s): Ogawa M, Mizuguchi K, Ishiguro A, Koyabu Y, Imai Y, Takahashi R, Mikoshina K, Aruga J
  • Journal Title: Gene Cells 13 Pages: 397-409
  • Peer Reviewed
• [Journal Article] L347P PINK1 mutant that fails to bind to Hsp90/cdc37 chaperones is rapidlydegraded in a proteasome-dependant manner. (2008)
  • Author(s): Moriwaki Y, KimY J, Ido Y, Misawa H, Kawashima K, Endo S, Takahashi, R.z
  • Journal Title: Neurosci. Res. 61 Pages: 43-48
  • Peer Reviewed
• [Journal Article] Cleveland DW Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. (2008)
  • Author(s): Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H
  • Journal Title: Nat.Neurosci. 11 Pages: 251-253
  • Peer Reviewed
• [Presentation] The establishment and analysis of 26S proteasome conditional knockout mice for the mechanisms of neurodegenerative diseases. (2010)
  • Author(s): Tashiro Y, Inoue H, Yamazaki M, Abe M, Ito H, Misawa H, Sakimura K, Takahashi R
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-08
• [Presentation] A high-throughput screening assay for drug discovery in SOD1-mediated ALS targeting the transcription of SOD1 (2010)
  • Author(s): Murakami G, Inoue H, Takahashi R
  • Organizer: The 40th Annual Meeting of Society for Neuroscience
  • Place of Presentation: San Diego, U.S.A.
  • Year and Date: 2010-11-17
• [Presentation] A high-throughput screening assay for drug discovery in SOD1-mediated ALS targeting the transcription of SOD1 (2010)
  • Author(s): Murakami G, Inoue H, Takahashi R
  • Organizer: The 33rd Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Kobe, Japan.
  • Year and Date: 2010-09-03
• [Presentation] 神経変性疾患モデル作製のための26Sプロテアソームコンディショナルノックアウトマウスの確立と解析 (2010)
  • Author(s): 田代善崇、井上治久、山崎真弥、阿部学、伊東秀文、三澤日出巳、崎村建司、高橋良輔
  • Organizer: 第33回日本神経科学大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-09-03
• [Presentation] Establishment of iPS cells from Amyotrophic lateral sclerosis model mice. (2010)
  • Author(s): Komatsu K, Inoue H, Kondo T, Kitaoka S, Ichisaka T, Takahashi K, Yamanaka S, Takahashi R
  • Organizer: The 33rd Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-09-02
• [Presentation] 家族性パーキンソン病の分子メカニズム-神経保護治療に向けて-シンポジウム神経変性疾患の分子標的治療への新たな展開」 (2009)
  • Author(s): 高橋良輔
  • Organizer: 第32回日本神経科学学会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-09-18
• [Presentation] パーキンソン病の最新の治療と展望。 (2009)
  • Author(s): 高橋良輔
  • Organizer: 平成21年度日本内科学会、生涯教育講演会
  • Place of Presentation: 仙台
  • Year and Date: 2009-09-06
• [Presentation] 孤発性パーキンソン病の病因:環境要因とリスク遺伝子。 (2009)
  • Author(s): 高橋良輔
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] シンポジウム「神経変性疾患関連遺伝子探索と機能解析」 (2008)
  • Author(s): Ryosuke Takahashi
  • Organizer: The molecular mechanisms underlying parkin-related parkinsonism, BMB2008
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-11
• [Presentation] 自律神経障害の新たな疾患概念;Autoimmune Autonomic Ganglionopathy (2008)
  • Author(s): 近藤孝之、井上治久、冨本秀和、高橋良輔
  • Organizer: 第61回日本自律神経学会総会、シンポジウム「自律神経学における最近のトピックス」
  • Place of Presentation: 横浜
  • Year and Date: 2008-11-07
• [Presentation] AANとMDSの取り組み (2008)
  • Author(s): 高橋良輔
  • Organizer: 第2回Movement Disorder Society, Japan学術集会、オープニングセミナー「パーキンソン病治療ガイドラインupdate」
  • Place of Presentation: 京都
  • Year and Date: 2008-10-02
• [Presentation] パーキンソン病における治療標的としての軸索再生 (2008)
  • Author(s): 井上治久、高橋良輔
  • Organizer: Neuroscience2008、シンポジウム「中枢神経系疾患に於ける軸索再生/変性のメカニズム」
  • Place of Presentation: 東京
  • Year and Date: 2008-07-09
• [Presentation] はじめに-神経変性疾患研究の課題 (2008)
  • Author(s): 高橋良輔
  • Organizer: 第49回日本神経学会総会シンポジウム「神経変性疾患研究の焦点-新たな病的因子の登場と臨床への展望」
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-16
• [Presentation] (2008)
  • Author(s): 河本恭裕、小林芳人、高橋良輔、秋口一郎
  • Organizer: alpha-synuclein関連疾患脳内の封入体におけるOmi/HtrA2の蓄積第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-15
• [Presentation] 慢性脳虚血はAβ沈着を促進する (2008)
  • Author(s): 北口浩史、冨本秀和、猪原匡史、植村健吾、木原武士、浅田めぐみ、木下彩栄、高橋良輔
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-15
• [Book] Protein Misforlding and Axonal Protection in Neurodegenerative, Disease Protein Folding and Misfolding : Neurodegenerative Diseases (2008)
  • Author(s): Inoue H, Kondo T, Lin L, Mi S, Isacson O, Takahashi R
  • Total Pages: 97-109
  • Publisher: Ovadi, J.and Orosz. F.Springer, Hungary
• [Remarks] ホームページ等
  • URL: http://www.kuhp.kyoto-u.ac.jp/.neurology/