Alzheimer disease modifier gene: Identification by novel transcriptions and functional analysis

• Project/Area Number: 26461747
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: Morihara Takashi 大阪大学, 医学系研究科, 助教 (90403196)
• Co-Investigator(Kenkyū-buntansha): 武田 雅俊 藍野大学, 公私立大学の部局等, 学長 (00179649) ; 田中 稔久 大阪大学, 医学系研究科, 准教授 (10294068)
• Co-Investigator(Renkei-kenkyūsha): AKATSU Hiroyasu 医療法人さわらび会福祉村病院, 長寿医療研究所, 研究員 (00399734) ; SUZUKI Toshiharu 北海道大学, 薬学研究科(研究院), 教授 (80179233) ; TSUNODA Tatsuhiko 独立行政法人理化学研究所, 統合生命医科学研究センター, グループディレクター (10273468)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: アルツハイマー病 / 疾患リスク遺伝子 / オミックス / アミロイドβ / マウス背景遺伝子 / トランスクリプトーム解析 / 網羅的解析 / モデル動物 / 疾患修飾遺伝子 / トランスクリプトーム / トランスレーショナル研究

Outline of Final Research Achievements

Genetic studies of common complex human diseases, including Alzheimer's disease (AD), are extremely resource intensive, yet have struggled to identify genes that are causal in disease. Combined with the costs of such studies and the inability to identify the “missing heritability” particularly in AD, alternate strategies warrant consideration. We devised a unique strategy that combines distinct mouse strains that vary naturally in amyloid beta (Abeta) production with transcriptomics to identify Klc1 splice variant E as a modifier of Abeta accumulation, a causative factor of AD. In AD patients, the expression levels of KLC1 variant E in brain were significantly higher compared to unaffected individuals. The identification of KLC1 variant E suggests that dysfunction of intracellular trafficking is causative in AD.

Research Products

• [Int'l Joint Research] Simon Fraser University(カナダ)
• [Int'l Joint Research] Simon Fraser University(カナダ)
• [Journal Article] Atlas stumbled: Kinesin light chain-1 variant E triggers a vicious cycle of axonal transport disruption and amyloid-β generation in Alzheimer's disease. (2015)
  • Author(s): Gan KJ, Morihara T(corresponding author), Silverman MA
  • Journal Title: Bioessays 37(2): 131-141, 2015 Volume: 37 Issue: 2 Pages: 131-141
  • DOI: 10.1002/bies.201400131
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as as amyloid beta accumulation modifier (2014)
  • Author(s): Morihara, T., Hayashi, N., Yokokoji, M., Akatsu, H., Silverman, MA., Kimura, N., Saito, Y., Suzuki, T., Yanagida, K., Tanaka, T., Kazui, H., Kudo, T., Kodama, TS., Sato, M., Hashimoto, R., Tagami, S., Okochi, M., Ytoh, N., Nishitomi, K., Takamura, H., Katayama, T., Hashizumi, Y., Kimura, R., Kamino, K., Takeda, M
  • Journal Title: Proc. Acad. Natl. Sci. USA Volume: 111 Issue: 7 Pages: 2638-2643
  • DOI: 10.1073/pnas.1307345111
  • Peer Reviewed / Open Access
• [Presentation] 脳内Aβ蓄積規定因子Kinesin Light Chain-1 variant E (KLC1vE) (2016)
  • Author(s): 森原剛史 佐藤真広 赤津裕康 Luc Paillard 林紀行 木村展之 鈴木利治 橋本亮太 柳田寛太 武田雅俊
  • Organizer: 第35回日本認知症学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-01
• [Presentation] 孤発性アルツハイマー病におけるAβ病理形成の新メカニズム (2016)
  • Author(s): 森原剛史
  • Organizer: 第15回関西・中部認知症研究会
  • Place of Presentation: 大阪
  • Year and Date: 2016-10-01
  • Invited
• [Presentation] Aβ脳蓄積の鍵の一つとなる遺伝子産物の同定とアルツハイマー病血中バイオマーカーの開発 (2016)
  • Author(s): 森原剛史、佐藤真広、赤津裕康、林紀行、Michael Silverman、Luc Paillard, 木村展之、橋本亮太、鈴木利治、柳田寛太、紙野晃人、武田雅
  • Organizer: 第58回日本老年医学会
  • Place of Presentation: 金沢
  • Year and Date: 2016-06-08
• [Presentation] 脳内Aβ蓄積量を規定する遺伝子産物KLC1vEの同定とその機能解析 (2015)
  • Author(s): "森原剛史 佐藤真広 赤津 Luc 林紀行 橋本亮太 柳田寛太 山口 角田達彦 武田雅俊 "
  • Organizer: 第60回 日本人類遺伝学会 2015.10.14-17
  • Place of Presentation: 東京
  • Year and Date: 2015-10-14
• [Presentation] 脳内Aβ蓄積量を規定する遺伝子産物KLC1vEの同定とその機能解析 (2015)
  • Author(s): 森原剛史 佐藤真広 赤津 Luc Paillard 林紀行 木村展之 鈴木利治 橋本亮太 柳田寛太 武田雅俊
  • Organizer: 第34回日本認知症学会学術集会
  • Place of Presentation: 青森
  • Year and Date: 2015-10-02
• [Presentation] Transcriptome analysis of distinct mouse strains reveals KLC1 splice variant E as an Abeta accumulation modifier (2015)
  • Author(s): T. Morihara, M. Sato, M. Silverman, H. Akatsu, N. Hayashi, M.. Yanagida, R. Hashimoto, H. T Suzuki T Tsunoda . Kamino, M. Takeda
  • Organizer: 第38回 日本神経科学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-07-28
• [Presentation] 遺伝子研究から見えてきたこと：アルツハイマー病理形成の原因としての細胞内輸送障害 (2014)
  • Author(s): 森原剛史、赤津裕康、佐藤真広、鈴木利治、木村展之、林紀行 、柳田寛太 、西道隆臣、紙野晃人 、武田雅俊
  • Organizer: 第３３回 日本認知症学会
  • Place of Presentation: パシフィコ横浜会議センター（神奈川）
  • Year and Date: 2014-11-29 – 2014-12-01
  • Invited
• [Presentation] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid beta pathology modifier in Alzheimer’s disease: A mouse-to-human translational approach to complex diseases (2014)
  • Author(s): T. Morihara, M. Sato, M. Silverman, H. Akatsu, N. Hayashi, M. Yokokoji, K. Yanagida, R. Hashimoto, H. Yamamori, T. Tsunoda, Y. Yamaguchi, K. Kamino, M. Takeda
  • Organizer: 64th Annual Meeting of the American Society of Human Genetics (ASHG 2014)
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-10-18 – 2014-10-22
• [Presentation] Identification of KLC1E as an Abeta accumulation modifier in Alzheimer’s disease：a novel approach to complex disease by transcriptome analysis of distinct mouse strains (2014)
  • Author(s): Morihara T
  • Organizer: ISN (International Society for Neurochemistry)- JSN (Japanese Society for Neurochemistry) Symposium (第57回日本神経化学大会・第36回日本生物学的精神医学会)
  • Place of Presentation: Nara Japan
  • Year and Date: 2014-09-29 – 2014-10-01
  • Invited
• [Presentation] アルツハイマー病のAβ病理を規定する因子：mouse-to-human translation研究戦略 (2014)
  • Author(s): 森原剛史
  • Organizer: 第３回大阪大学神経難病フォーラム
  • Place of Presentation: 大阪大学銀杏会館（大阪）
  • Year and Date: 2014-08-09
  • Invited
• [Presentation] Transcriptome analysis of distinct mouse strains reveals KLC1 splice variant E as an Abeta accumulation modifier (2014)
  • Author(s): T. Morihara, N. Hayashi, H. Akatsu, M. Silverman, M. Yokokoji, N. Kimura, M. Sato, K. Kamino, Y. Yamagichi, T. Tsunoda, T. Tanaka, M. Takeda
  • Organizer: Alzheimer’s Assosication International Conference (AAIC)
  • Place of Presentation: Copenhagen,Denmark
  • Year and Date: 2014-07-12 – 2014-07-17
• [Remarks] 大阪大学精神医学教室 神経化学グループ
  • URL: http://www2.med.osaka-u.ac.jp/psy/laboratories/lab01/amyloidbeta.html