タンパク分解系障害による脳内環境変調と神経変性メカニズム

2015 Fiscal Year Annual Research Report

• Project Area: Brain Environment
• Project/Area Number: 23111002
• Research Institution: Kyoto University
• Principal Investigator: 高橋 良輔 京都大学, 医学(系)研究科(研究院), 教授 (90216771)
• Co-Investigator(Kenkyū-buntansha): 漆谷 真 京都大学, 医学(系)研究科(研究院), 准教授 (60332326)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Keywords: 脳神経疾患 / 神経科学 / 遺伝子 / 内科 / トランスレーショナルリサーチ

Outline of Annual Research Achievements

1)ゴーシェ病の原因遺伝子であるGBAの変異は、孤発性PDの強力な遺伝的リスクであることが知られている。本研究ではGBA欠失メダカを作製し、その表現型を解析した。同変異メダカは２ヵ月齢で回転する異常行動を示し、５ヵ月齢までに死亡した。脳の病理学的な解析では、非選択的な神経細胞脱落と神経炎症を認めた。また、神経細胞においてリソソームの異常とオートファゴソームの蓄積を伴った軸索の腫脹を認め、後者に一致してα-シヌクレインの蓄積を認めた。以上から、同変異体におけるα-シヌクレイン蓄積の病態としてオートファジー・リソソーム経路の障害や軸索輸送の障害の関与を考えた。これらの結果は、GBA欠失メダカが新規の神経型ゴーシェ病モデルとして、またPDの病態解明において、今後の研究に有用である可能性を示した（Uemura N et al., PLoS Genetics 2015）。
2)我々は運動ニューロン特異的なRpt3欠損マウス(Rpt3-CKOマウス)を確立している。Rpt3-CKOマウスはUPSの破綻から運動ニューロン死を起こすが、この病態機序の解明を目的としてRpt3-CKOマウスの運動ニューロンをレーザーマイクロダイセクションで切り取り、マイクロアレイによる解析を行った。マイクロアレイによる比較解析と組織免疫染色により、Rpt3-CKOマウスでストレス応答分子であるNdrg1の発現増加が示唆された。同様に、組織免疫染色により家族性ALSモデルマウスである変異SOD1過剰発現マウスにおいてNdrg1の発現増加が観察された。Ndrg1は同じ神経変性疾患であるシャルコー・マリー・トゥース病の原因遺伝子としても知られており、またNdrg1欠損マウスは神経障害を引き起こすことから、Ndrg1の発現誘導はニューロンにとって保護的に働いていることが予想された。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Network specific change in white matter integrity in mesial temporal lobe epilepsy. (2016)
  • Author(s): Imamura H, Matsumoto R, Takaya S, Nakagawa T, Shimotake A, Kikuchi T, Sawamoto N, Kunieda T, Mikuni N, Miyamoto S, Fukuyama H, Takahashi R, Ikeda A.
  • Journal Title: Epilepsy Res. Volume: 120 Pages: 65-72
  • DOI: 10.1016/j.eplepsyres.2015.12.003.
  • Peer Reviewed
• [Journal Article] CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS. (2016)
  • Author(s): Uchida T, Tamaki Y, Ayaki T, Shodai A, Kaji S, Morimura T, Banno Y, Nishitsuji K, Sakashita N, Maki T, Yamashita H, Ito H, Takahashi R, Urushitani M.
  • Journal Title: Sci Rep. Volume: 6 Pages: 19118
  • DOI: 10.1038/srep19118.
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cells in Parkinson's disease: scientific and clinical challenges. (2016)
  • Author(s): Xiao B, Ng HH, Takahashi R, Tan EK.
  • Journal Title: J Neurol Neurosurg Volume: 0 Pages: 0
  • DOI: 10.1136/jnnp-2015-312036.
  • Peer Reviewed
• [Journal Article] Benign adult familial myoclonus epilepsy is a progressive disorder: no longer idiopathic generalized epilepsy. (2016)
  • Author(s): Hitomi T, Kobayashi K, Sakurai T, Ueda S, Jingami N, Kanazawa K, Matsumoto R, Takahashi R, Ikeda A.
  • Journal Title: Epileptic Disord. Volume: 18(1) Pages: 67-72
  • DOI: 10.1684/epd.2016.0807.
  • Peer Reviewed
• [Journal Article] Idiopathic normal pressure hydrocephalus has a different cerebrospinal fluid biomarker profile from Alzheimer's disease. (2015)
  • Author(s): Jingami N, Asada-Utsugi M, Uemura K, Noto R, Takahashi M, Ozaki A, Kihara T, Kageyama T, Takahashi R, Shimohama S, Kinoshita A.
  • Journal Title: J Alzheimers Dis. Volume: 45(1) Pages: 109-115
  • DOI: 10.3233/JAD-142622.
  • Peer Reviewed
• [Journal Article] Task-specific brain reorganization in motor recovery induced by a hybrid-rehabilitation combining training with brain stimulation after stroke. (2015)
  • Author(s): Koganemaru S, Sawamoto N, Aso T, Sagara A, Ikkaku T, Shimada K, Kanematsu M, Takahashi R, Domen K, Fukuyama H, Mima T.
  • Journal Title: Neurosci Res. Volume: 92 Pages: 29-38
  • DOI: 10.1016/j.neures.2014.10.004.
  • Peer Reviewed
• [Journal Article] Direct Exploration of the Role of the Ventral Anterior Temporal Lobe in Semantic Memory: Cortical Stimulation and Local Field Potential Evidence From Subdural Grid Electrodes. (2015)
  • Author(s): Shimotake A, Matsumoto R, Ueno T, Kunieda T, Saito S, Hoffman P, Kikuchi T, Fukuyama H, Miyamoto S, Takahashi R, Ikeda A, Lambon Ralph MA.
  • Journal Title: Cereb Cortex Volume: 25(10) Pages: 3802-17
  • DOI: 10.1093/cercor/bhu262.
  • Peer Reviewed
• [Journal Article] SIRT1 attenuates severe ischemic damage by preserving cerebral blood flow. (2015)
  • Author(s): Hattori Y, Okamoto Y, Nagatsuka K, Takahashi R, Kalaria RN, Kinoshita M, Ihara M.
  • Journal Title: Neuroreport. Volume: 26(3) Pages: 113-117
  • DOI: 10.1097/WNR.0000000000000308.
  • Peer Reviewed
• [Journal Article] Possible induction of multiple seizure foci due to parietal tumour and anti-NMDAR antibody. (2015)
  • Author(s): Matsumoto R, Mikuni N, Tanaka K, Usami K, Fukao K, Kunieda T, Takahashi Y, Miyamoto S, Fukuyama H, Takahashi R, Ikeda A.
  • Journal Title: Epileptic Disord. Volume: 17(1) Pages: 89-94
  • DOI: 10.1684/epd.2015.0725.
  • Peer Reviewed
• [Journal Article] Parkinson's disease patients showed delayed awareness of motor intention. (2015)
  • Author(s): Tabu H, Aso T, Matsuhashi M, Ueki Y, Takahashi R, Fukuyama H, Shibasaki H, Mima T.
  • Journal Title: Neurosci Res. Volume: 95 Pages: 74-77
  • DOI: 10.1016/j.neures.2015.01.012.
  • Peer Reviewed
• [Journal Article] Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. (2015)
  • Author(s): Uemura N, Koike M, Ansai S, Kinoshita M, Ishikawa-Fujiwara T, Matsui H, Naruse K, Sakamoto N, Uchiyama Y, Todo T, Takeda S, Yamakado H, Takahashi R
  • Journal Title: PLoS Genet. Volume: 11(4) Pages: e1005065
  • DOI: 10.1371/journal.pgen.1005065.
  • Peer Reviewed
• [Journal Article] Risk Factors for Infective Complications with Long-Term Subdural Electrode Implantation in Patients with Medically Intractable Partial Epilepsy. (2015)
  • Author(s): Shibata S, Kunieda T, Inano R, Sawada M, Yamao Y, Kikuchi T, Matsumoto R, Ikeda A, Takahashi R, Mikuni N, Takahashi J, Miyamoto S.
  • Journal Title: World Neurosurg. Volume: 84(2) Pages: 320-326
  • DOI: 10.1016/j.wneu.2015.03.048.
  • Peer Reviewed
• [Journal Article] Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. (2015)
  • Author(s): Maki T, Maeda M, Uemura M, Lo EK, Terasaki Y, Liang AC, Shindo A, Choi YK, Taguchi A, Matsuyama T, Takahashi R, Ihara M, Arai K.
  • Journal Title: Neurosci Lett. Volume: 597 Pages: 164-169
  • DOI: 10.1016/j.neulet.2015.04.047.
  • Peer Reviewed
• [Journal Article] Different Mode of Afferents Determines the Frequency Range of High Frequency Activities in the Human Brain: Direct Electrocorticographic Comparison between Peripheral Nerve and Direct Cortical Stimulation. (2015)
  • Author(s): Kobayashi K, Matsumoto R, Matsuhashi M, Usami K, Shimotake A, Kunieda T, Kikuchi T, Mikuni N, Miyamoto S, Fukuyama H, Takahashi R, Ikeda A.
  • Journal Title: PLoS One. Volume: 10(6) Pages: e0130461
  • DOI: 10.1371/journal.pone.0130461.
  • Peer Reviewed
• [Journal Article] Increased GADD34 in oligodendrocytes in Alzheimer's disease. (2015)
  • Author(s): Honjo Y, Ayaki T, Tomiyama T, Horibe T, Ito H, Mori H, Takahashi R, Kawakami K
  • Journal Title: Neurosci Lett. Volume: 602 Pages: 50-55
  • DOI: 10.1016/j.neulet.2015.06.052.
  • Peer Reviewed
• [Journal Article] Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism. (2015)
  • Author(s): Kitao Y, Ageta-Ishihara N, Takahashi R, Kinoshita M, Hori O.
  • Journal Title: F1000Research Volume: 4 Pages: 130
  • DOI: 10.12688/f1000research.6386.1.
  • Peer Reviewed
• [Journal Article] Sleep modulates cortical connectivity and excitability in humans: Direct evidence from neural activity induced by single-pulse electrical stimulation. (2015)
  • Author(s): Usami K, Matsumoto R, Kobayashi K, Hitomi T, Shimotake A, Kikuchi T, Matsuhashi M, Kunieda T, Mikuni N, Miyamoto S, Fukuyama H, Takahashi R, Ikeda A.
  • Journal Title: Hum Brain Mapp. Volume: 36(11) Pages: 4714-4729
  • DOI: 10.1002/hbm.22948.
  • Peer Reviewed
• [Journal Article] The Parkinson's Disease-Associated Protein Kinase LRRK2 Modulates Notch Signaling through the Endosomal Pathway. (2015)
  • Author(s): Imai Y, Kobayashi Y, Inoshita T, Meng H, Arano T, Uemura K, Asano T, Yoshimi K, Zhang CL, Matsumoto G, Ohtsuka T, Kageyama R, Kiyonari H, Shioi G, Nukina N, Hattori N, Takahashi R.
  • Journal Title: PLoS Genet. Volume: 11(9) Pages: e1005503
  • DOI: 10.1371/journal.pgen.1005503.
  • Peer Reviewed
• [Journal Article] Use of a new generation of adaptive servo ventilation for sleep-disordered breathing in patients with multiple system atrophy. (2015)
  • Author(s): Hamada S, Takahashi R, Mishima M, Chin K.
  • Journal Title: BMJ Case Rep. Volume: 6 Pages: 2015
  • DOI: 10.1136/bcr-2014-206372.
  • Peer Reviewed
• [Journal Article] The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease. (2015)
  • Author(s): Watanabe K, Uemura K, Asada M, Maesako M, Akiyama H, Shimohama S, Takahashi R, Kinoshita A.
  • Journal Title: Mol Brain. Volume: 8(1) Pages: 82
  • DOI: 10.1186/s13041-015-0174-2.
  • Peer Reviewed
• [Journal Article] Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory. (2015)
  • Author(s): Kitamura A, Saito S, Maki T, Oishi N, Ayaki T, Hattori Y, Yamamoto Y, Urushitani M, Kalaria RN, Fukuyama H, Horsburgh K, Takahashi R, Ihara M.
  • Journal Title: J Cereb Blood Flow Metab. Volume: 0 Pages: 0
  • Peer Reviewed
• [Journal Article] Multiple neurological abnormalities, including pontine hemorrhage, multiple sclerosis and aseptic meningitis, during anti-TNF-α therapy in psoriatic arthritis. (2015)
  • Author(s): Honda Y, Otsuka A, Egawa G, Inoue Y, Kuzuya A, Takahashi R, Miyachi Y, Kabashima K.
  • Journal Title: Eur J Dermatol. Volume: 25(5) Pages: 487-488
  • DOI: 10.1684/ejd.2015.2558.
  • Peer Reviewed
• [Journal Article] Deletion of Atf6α enhances kainate-induced neuronal death in mice. (2015)
  • Author(s): Kezuka D, Tkarada-Iemata M, Hattori T, Mori K, Takahashi R, Kitao Y, Hori O.
  • Journal Title: Neurochem Int. Volume: 92 Pages: 67-74.
  • DOI: 10.1016/j.neuint.2015.12.009.
  • Peer Reviewed
• [Journal Article] Deletion of Atf6α impairs astroglial activation and enhances neuronal death following brain ischemia in mice. (2015)
  • Author(s): Yoshikawa A, Kamide T, Hashida K, Ta HM, Inahata Y, Takarada-Iemata M, Hattori T, Mori K, Takahashi R, Matsuyama T, Hayashi Y, Kitao Y, Hori O.
  • Journal Title: J Neurochem. Volume: 132(3) Pages: 342-353
  • DOI: 10.1111/jnc.12981.
  • Peer Reviewed
• [Presentation] Fish model of Parkinson’s disease. (2016)
  • Author(s): Takahashi R
  • Organizer: Keio Longevity Seminar Series “Resilience in Brain Agin –From Model Systems of Neurodegenerastion to Supercentenarian Study” Keio Longevity Initiative Seminar Series,
  • Place of Presentation: 東京
  • Year and Date: 2016-02-18 – 2016-02-18
  • Invited
• [Presentation] The Mechanism of Motor Neuron Degeneration in Ubiquitin Proteasome System Dysfunction (2015)
  • Author(s): 星野 友則、Yamashita H, Tashiro Y, Misawa H, Makoto U, Takahashi R
  • Organizer: BMB2015
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-02 – 2015-12-02
• [Presentation] Parkinson Disease Treatment: Current Perspective and Future Directions.(Plenary Lecture) (2015)
  • Author(s): Takahashi R
  • Organizer: ASEAN 2015 Neuroscience
  • Place of Presentation: Singapore
  • Year and Date: 2015-07-30 – 2015-07-31
  • Invited
• [Presentation] FUS遺伝子変異を伴う筋萎縮性側索硬化症の臨床像：若年発症例を含む4症例の検討. (2015)
  • Author(s): 引網亮太,, 端祐一郎, 山門穂高, 辰己 新水, 山下博史, 澤本伸克, 辻輝之, 川本未知, 幸原伸夫, 井上治久, 漆谷真, 高橋良輔.
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-23 – 2015-05-23
• [Presentation] Creating mice models for Parkinson's disease based on its genetic risk factors (2015)
  • Author(s): 生野 真嗣、浅野剛史、山門穂高、高橋良輔
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-23 – 2015-05-23
• [Presentation] VHL とCUL2; TDP-43 の凝集を促進するVHL と分解を促進するCUL2. TDP-43 proteinopathy におけるVHL の2 面性. (2015)
  • Author(s): 内田 司, 玉木良高, 小代明美, 綾木 孝, 守村敏史, 辰巳新水, 伊東秀文, 坂下 直実, 高橋良輔, 漆谷真.
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-22 – 2015-05-22
• [Presentation] Immunohistochemical localization of HAX-1 and PALR in Lewy bodies in PD and DLB. (2015)
  • Author(s): 河本恭裕、辰己新水、漆谷 真、伊東秀文、髙橋良輔.
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-22 – 2015-05-22
• [Presentation] Analysis of the ATP13A2mutant (PARK9) medaka (Oryziaslatipes) (2015)
  • Author(s): 樽野 陽亮、松井秀明 上村紀仁 山門穂高 髙橋良輔
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-22 – 2015-05-22
• [Presentation] 多発性硬化症患者におけるTLR/CD40刺激によるB細胞サイトカインの解析 (2015)
  • Author(s): 岡田洋一郎、藤井ちひろ、端祐一郎、越智博文、中川正法、水野敏樹、松本禎之、漆谷 真、髙橋良輔、近藤誉之.
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21 – 2015-05-21
• [Presentation] Clinicopathologic study of autopsied familial ALS cases with optineurin mutation. (2015)
  • Author(s): 綾木 孝, 伊東秀文、小牟禮修、辰己新水、鎌田正紀、漆谷 真、川上秀史、髙橋良輔.
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21 – 2015-05-21
• [Presentation] ApoE Isoforms Differentially Affect Amyloid beta-Induced Synaptic Toxicity (2015)
  • Author(s): 上村 麻衣子、植村健吾、木下彩栄、高橋良輔
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21 – 2015-05-21
• [Presentation] Hereditary Diffuse Leukoencephalopathy with Spheroids: A Hidden Culprit. (2015)
  • Author(s): 梶 誠兒、沖亮祐、宮本亮介、瓦井俊孝、和泉唯信、梶龍兒、高橋良輔
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21 – 2015-05-21
• [Presentation] Microarray analysis in Motor Neuron-Specific 26S Proteasome Conditional KO Mice (2015)
  • Author(s): 星野 友則、Yamashita H, Tashiro Y, Misawa H, Takahashi R
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-21
• [Presentation] Gaucher disease model in medaka displays axonal accumulation of alpha-synuclein (2015)
  • Author(s): 上村紀仁
  • Organizer: 第56回日本神経学会 学術集会
  • Place of Presentation: 新潟
  • Year and Date: 2015-05-20 – 2015-05-20