FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization

Tsuyoshi Udagawa, Yusuke Fujioka, Motoki Tanaka, Daiyu Honda, Satoshi Yokoi, Yuichi Riku, Daisuke Ibi, Taku Nagai, Kiyofumi Yamada, Hirohisa Watanabe, Masahisa Katsuno, Toshifumi Inada, Kinji Ohno, Masahiro Sokabe, Haruo Okado, Shinsuke Ishigaki, Gen Sobue

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58 Citations (Scopus)

Abstract

FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3′ terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours.

Original languageEnglish
Article number7098
JournalNature communications
Volume6
DOIs
Publication statusPublished - 13-05-2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Udagawa, T., Fujioka, Y., Tanaka, M., Honda, D., Yokoi, S., Riku, Y., Ibi, D., Nagai, T., Yamada, K., Watanabe, H., Katsuno, M., Inada, T., Ohno, K., Sokabe, M., Okado, H., Ishigaki, S., & Sobue, G. (2015). FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization. Nature communications, 6, [7098]. https://doi.org/10.1038/ncomms8098