EEstablishment of treatment target for ALS / FTLD

• Project/Area Number: 15K09323
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Keio University
• Principal Investigator: Ito Daisuke 慶應義塾大学, 医学部(信濃町), 講師 (80286450)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 筋萎縮性側策硬化症 / 前頭側頭葉変性症 / optineurin / ubiquilin2 / 前頭側頭型認知症 / FUS / RNA結合蛋白 / 筋萎縮性側索硬化症 / TDP-43

Outline of Final Research Achievements

1) Two different molecules involved in familial ALS, UBQLN 2 and OPTN are both involved in endosomal vesicles involved in proteolysis, have the function of connecting enodosome and autopahgy, and formed a novel protein quality control mechanism in endosome. 2) In DRP (dipeptidere peat protein) by non-AUG (RAN) translation from abnormal elongation GGGGCC repetitive sequence, expression of poly-PR, which is strongly basic, significantly reduces gemini of coiled bodies and Cajal bodies into Hela cells and suggested that it reflects the pathology of ALS.

Research Products

• [Journal Article] Dendritic Homeostasis Disruption in a Novel Frontotemporal Dementia Mouse Model Expressing Cytoplasmic Fused in Sarcoma (2017)
  • Author(s): Shiihashi Gen、Ito Daisuke、Arai Itaru、Kobayashi Yuki、Hayashi Kanehiro、Otsuka Shintaro、Nakajima Kazunori、Yuzaki Michisuke、Itohara Shigeyoshi、Suzuki Norihiro
  • Journal Title: EBioMedicine Volume: 24 Pages: 102-115
  • DOI: 10.1016/j.ebiom.2017.09.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] De novo design of RNA-binding proteins with a prion-like domain related to ALS/FTD proteinopathies. (2017)
  • Author(s): Mitsuhashi K, Ito D, Mashima K, Oyama M, Takahashi S, Suzuki N
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 16871-16871
  • DOI: 10.1038/s41598-017-17209-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extremely Low Prevalence of Amyloid Positron Emission Tomography Positivity in Parkinson's Disease without Dementia. (2017)
  • Author(s): Mashima K, Ito D, Kameyama M, Osada T, Tabuchi H, Nihei Y, Yoshizaki T, Noguchi E, Tanikawa M, Iizuka T, Date Y, Ogata Y, Nakahara T, Iwabuchi Y, Jinzaki M, Murakami K, Suzuki N
  • Journal Title: Eur Neurol Volume: 77 Issue: 5-6 Pages: 231-237
  • DOI: 10.1159/000464322
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The psychological impact of disclosing amyloid status to Japanese elderly: a preliminary study on asymptomatic patients with subjective cognitive decline (2017)
  • Author(s): Wake Taisei、Tabuchi Hajime、Funaki Kei、Ito Daisuke、Yamagata Bun、Yoshizaki Takahito、Kameyama Masashi、Nakahara Tadaki、Murakami Koji、Jinzaki Masahiro、Mimura Masaru
  • Journal Title: International Psychogeriatrics Volume: Epub ahead of print Issue: 5 Pages: 1-5
  • DOI: 10.1017/s1041610217002204
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2. (2016)
  • Author(s): Osaka M, Ito D, Suzuki N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 472(2) Issue: 2 Pages: 324-31
  • DOI: 10.1016/j.bbrc.2016.02.107
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mislocated FUS is sufficient for gain-of-toxic-function amyotrophic lateral sclerosis phenotypes in mice (2016)
  • Author(s): Shiihashi G, Ito D, Yagi T, Nihei Y, Ebine T, Suzuki N
  • Journal Title: BRAIN Volume: 139 Issue: 9 Pages: 2380-2394
  • DOI: 10.1093/brain/aww161
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TFG-Related Neurologic Disorders: New Insights Into Relationships Between Endoplasmic Reticulum and Neurodegeneration. (2016)
  • Author(s): Yagi T, Ito D.
  • Journal Title: J Neuropathol Exp Neurol. Volume: 2016
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS (2015)
  • Author(s): Mai Yamakawa, Daisuke Ito, Takao Honda, Ken-ichiro Kubo, Mariko Noda, Kazunori Nakajima, and Norihiro Suzuki
  • Journal Title: Hum. Mol. Genet. Volume: 24 Issue: 6 Pages: 1630-1645
  • DOI: 10.1093/hmg/ddu576
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Evidence of a link between ubiquilin 2 and optineurin in amyotrophic lateral sclerosis. (2015)
  • Author(s): Osaka M, Ito D, Yagi T, Nihei Y, Suzuki N.
  • Journal Title: Hum Mol Genet. Volume: 24(6) Issue: 6 Pages: 1617-29
  • DOI: 10.1093/hmg/ddu575
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Novel FTD model mice expressed cytoplasmic FUS in a toxic gain of function manner. (2017)
  • Author(s): Shiihashi G, Ito D, Hayashi Y, Itohara S, Hayashi K, Nakajima K, Otsuka S, Yuzaki M, Suzuki N.
  • Organizer: The 13th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders,
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-03-31
  • Int'l Joint Research
• [Presentation] Novel FTD model mice expressed cytoplasmic FUS in a toxic gain of function manner (2017)
  • Author(s): 16)Shiihashi G, Ito D, Hayashi Y, Itohara S, Hayashi K, Nakajima K, Otsuka S, Yuzaki M, Suzuki N
  • Organizer: The 13th International Conference on Alzheimer's and Parkinson's Diseases and Related Neurological Disorders
  • Int'l Joint Research
• [Presentation] A novel ALS/FTD model mouse expressing cytoplasmic mutant fus leads neurodegeneration via dendritic homeostasis disruption (2017)
  • Author(s): Shiihashi G, Ito D, Arai I, Kobayashi Y, Hayashi K, Otsuka S, Nakajima K, Yuzaki M, Itohara S, Suzuki N
  • Organizer: The XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research
• [Presentation] De novo design of a cytoplasmic RNA-binding protein with a prion-like domain related to ALS/FTD proteinopathies (2017)
  • Author(s): Mitsuhashi K, Ito D, and Suzuki N
  • Organizer: The XXIII World Congress of Neurology (WCN 2017)
  • Int'l Joint Research
• [Presentation] Novel FTD model mice expressed cytoplasmic FUS in a toxic gain of function manner. (2016)
  • Author(s): Shiihashi G, ItoD, Yagi T, Nihei Y, Kobayashi Y, Itohara S, Suzuki N.
  • Organizer: 第35回日本認知症学会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2016-12-01
• [Presentation] Mislocated FUS is sufficient condition to lead ALS/FTD-phenotype in a dominant gain-of-function manner (2016)
  • Author(s): Ito D, Shiihashi G, Yagi T, Nihei Y, Kobayashi Y, Itohara S, Suzuki N.
  • Organizer: 11th Brain Research Conference, RNA Metabolism in Neurological Disease.
  • Place of Presentation: Chicago, USA
  • Year and Date: 2016-11-15
  • Int'l Joint Research
• [Presentation] Toxic gain of function is sufficient condition in FUS proteinopathy. (2016)
  • Author(s): Shiihashi G, Ito D, Yagi T , Nihei Y, Ebine T, Suzuki N.
  • Organizer: 4th International Conference on Molecular Neurodegeneration (ICMN 2016)
  • Place of Presentation: San Diego, USA,
  • Year and Date: 2016-05-09
  • Int'l Joint Research
• [Presentation] Toxic gain of function is sufficient condition in FUS proteinopathy. (2016)
  • Author(s): Shiihashi G, Ito D, Yagi T , Nihei Y, Ebine T, Suzuki N.
  • Organizer: 4th International Conference on Molecular Neurodegeneration (ICMN 2016)
  • Place of Presentation: Soul, Korea
  • Year and Date: 2016-05-09
  • Int'l Joint Research
• [Presentation] Impact of dipeptide repeat protein with Cytotoxic properties on c9FTD/ALS. (2015)
  • Author(s): Ito D, Yamakawa M, Suzuki N.
  • Organizer: 10th Brain Research Conference, RNA Metabolism in Neurological Disease.
  • Place of Presentation: シカゴ (米国)
  • Year and Date: 2015-10-10
  • Int'l Joint Research
• [Presentation] Evidence that toxic gain of function is sufficient condition in FUS proteinopathy (2015)
  • Author(s): Shiihashi G, Ito D, Yagi T , Nihei Y, Ebine T, Suzuki N.
  • Organizer: 第34回日本認知症学会
  • Place of Presentation: リンクステーション青森 （青森県青森市）
  • Year and Date: 2015-10-02
• [Presentation] Cytotoxic properties of dipeptide repeat proteins generated by repeatassociated, nonATG（RAN）translation on c9ALSFT. (2015)
  • Author(s): Daisuke Ito.
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ （埼玉県大宮市）
  • Year and Date: 2015-09-11
  • Invited
• [Book] 認知症 専門医が教える最新事情 (2017)
  • Author(s): 伊東大介
  • Total Pages: 205
  • Publisher: 講談社
  • ISBN: 9784062915137