title: FUS regulates AMPA receptor function and FTLD/ALS-associated behaviour via GluA1 mRNA stabilization.
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.
authors.affiliation: 1] Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan [2] Graduate School of pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Udagawa
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Fujioka
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Motoki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Daiyu
authors.initials: D
authors.lastname: Honda
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yokoi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Riku
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ibi
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Graduate School of pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Inada
authors.affiliation: Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Kinji
authors.initials: K
authors.lastname: Ohno
authors.affiliation: Mechanobiology Laboratory, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Masahiro
authors.identifier: 0000000177910166
authors.initials: M
authors.lastname: Sokabe
authors.affiliation: Department of Brain Development and Neural Regeneration, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Okado
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*
chemical_list: C000599551:FUS protein, mouse; D021122:Protein Subunits; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D018091:Receptors, AMPA