Loss of function of FUS/TLS in normal and pathological conditions

• Project/Area Number: 25461299
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Meiji Pharmaceutical University (2014-2016); Institute of Physical and Chemical Research (2013)
• Principal Investigator: Kino Yoshihiro 明治薬科大学, 薬学部, 講師 (80415140)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: FUS/TLS / ALS / FTD / ノックアウトマウス / 神経変性疾患 / ポリグルタミン病 / RNA結合タンパク質 / ハンチントン病 / ＡＬＳ / ＦＴＤ / ＦＵＳ／ＴＬＳ / ＲＮＡ結合タンパク質 / 分子生物学

Outline of Final Research Achievements

FUS/TLS is an RNA-binding protein associated with neurodegenerative diseases. Mutations of FUS/TLS are causative of amyotrophic lateral sclerosis (ALS), while FUS/TLS protein is accumulated in the inclusion bodies of a subset of frontotemporal lobar degeneration and polyglutamine diseases. However, pathological roles of FUS/TLS in these diseases have been elusive. We made homozygous FUS/TLS knockout mice, which showed some behavioral alterations but did not manifest ALS-like phenotypes. We then crossed TLS heterozygous mice with Huntington’s disease model mice and found that FUS/TLS heterozygosity worsened the HD phenotypes. In conclusion, our results indicate that loss of FUS/TLS function is not sufficient for causing ALS, while reduced function of FUS/TLS can modify the disease severity of HD.

Research Products

• [Int'l Joint Research] University of Manitoba(カナダ)
• [Journal Article] FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice. (2016)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Yamada M, Doi H, Takumi T, Adachi H, Katsuno M, Sobue G, Hicks GG, Hattori N, Shimogori T, Nukina N.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 35236-35236
  • DOI: 10.1038/srep35236
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] FUS/TLS deficiency causes behavioral and pathological abnormalities distinct from amyotrophic lateral sclerosis. (2015)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Yamada M, Miyazaki H, Akagi T, Hashikawa T, Doi H, Takumi T, Hicks GG, Hattori N, Shimogori T, Nukina N.
  • Journal Title: Acta Neuropathol Commun Volume: 3 Issue: 1 Pages: 24-24
  • DOI: 10.1186/s40478-015-0202-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Nuclear localization of MBNL1: splicing-mediated autoregulation and repression of repeat-derived aberrant proteins. (2015)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Oma Y, Hattori N, Ishiura S, Nukina N.
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 3 Pages: 740-56
  • DOI: 10.1093/hmg/ddu492
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dexamethasone induces heat shock response and slows down disease progression in mouse and fly models of Huntington's disease (2014)
  • Author(s): Maheshwari, M., Bhutani, S., Das, A., Mukherjee, R., Sharma, A., Kino, Y., Nukina, N. & Jana, N.R.
  • Journal Title: Hum. Mol. Genet. Volume: 23 Issue: 10 Pages: 2737-2751
  • DOI: 10.1093/hmg/ddt667
  • Peer Reviewed
• [Journal Article] Cyclin-dependent kinase 5 phosphorylates and induces the degradation of ataxin-2 (2014)
  • Author(s): Asada, A., Yamazaki, R., Kino, Y., Saito, T., Kimura, T., Miyake, M., Hasegawa, M., Nukina, N. & Hisanaga, S.
  • Journal Title: Neurosci. Lett. Volume: 563 Pages: 112-117
  • DOI: 10.1016/j.neulet.2014.01.046
  • Peer Reviewed
• [Journal Article] FUS/TLS (2014)
  • Author(s): 紀 嘉浩、貫名 信行
  • Journal Title: 医学のあゆみ 医学・医療のいまがわかるキーワード 2014 Volume: 249 Pages: 438-438
• [Presentation] Genetic effetcs of FUS/TLS heterozygous deletion on polyglutamine disease model mice (2016)
  • Author(s): Kino Y, Washizu C, Kurosawa M, Yamada M, Doi H, Takumi T, Adachi H, Katsuno M, Sobue G, Geoffrey G. Hicks GG, Hattori N, Shimogori T, Nukina N.
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
• [Presentation] 病態制御因子としてのポリグルタミン凝集体結合タンパク質 (2014)
  • Author(s): 紀 嘉浩、貫名 信行
  • Organizer: 第37回日本神経科学大会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-11 – 2014-09-13
  • Invited