title: Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif.
abstract: Mutations to the RNA binding protein, fused in sarcoma (FUS) occur in ∼5% of familial ALS and FUS-positive cytoplasmic inclusions are commonly observed in these patients. Altered RNA metabolism is increasingly implicated in ALS, yet it is not understood how the specificity with which FUS interacts with RNA in the cytoplasm can affect its aggregation in vivo. To further understand this, we expressed, in mice, a form of FUS (FUS ΔRRMcyt) that lacked the RNA recognition motif (RRM), thought to impart specificity to FUS-RNA interactions, and carried an ALS-associated point mutation, R522G, retaining the protein in the cytoplasm. Here we report the phenotype and results of histological assessment of the brain of transgenic mice expressing this isoform of FUS. Results demonstrated that neuronal expression of FUS ΔRRMcyt caused early lethality often preceded by severe tremor. Large FUS-positive cytoplasmic inclusions were found in many brain neurons; however, neither neuronal loss nor neuroinflammatory response was observed. In conclusion, the extensive FUS proteinopathy and severe phenotype of these mice suggests that affecting the interactions of FUS with RNA in vivo may augment its aggregation in the neuronal cytoplasm and the severity of disease processes.
authors.affiliation: a School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue , Cardiff , UK.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Robinson
authors.affiliation: b Institute of Gene Biology, Russian Academy of Sciences , Moscow , Russian Federation.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Deykin
authors.affiliation: c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Evgeny V
authors.initials: EV
authors.lastname: Bronovitsky
authors.affiliation: c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Ruslan K
authors.initials: RK
authors.lastname: Ovchinnikov
authors.affiliation: a School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue , Cardiff , UK.|c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Ustyugov
authors.affiliation: a School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue , Cardiff , UK.|c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Shelkovnikova
authors.affiliation: c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Michail S
authors.initials: MS
authors.lastname: Kukharsky
authors.affiliation: b Institute of Gene Biology, Russian Academy of Sciences , Moscow , Russian Federation.
authors.forename: Tatyana G
authors.initials: TG
authors.lastname: Ermolkevich
authors.affiliation: b Institute of Gene Biology, Russian Academy of Sciences , Moscow , Russian Federation.
authors.forename: Igor L
authors.initials: IL
authors.lastname: Goldman
authors.affiliation: b Institute of Gene Biology, Russian Academy of Sciences , Moscow , Russian Federation.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Sadchikova
authors.affiliation: d Pirogov Russian National Research Medical University , Moscow , Russian Federation.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Kovrazhkina
authors.affiliation: c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Sergey O
authors.initials: SO
authors.lastname: Bachurin
authors.affiliation: a School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue , Cardiff , UK.
authors.forename: Vladimir L
authors.initials: VL
authors.lastname: Buchman
authors.affiliation: a School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue , Cardiff , UK.|c Institute of Physiologically Active Compounds Russian Academy of Sciences , Chernogolovka, Moscow Region , Russian Federation.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Ninkina
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D053609:Lethargy / Q000150:complications / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D014202:Tremor / Q000235:genetics / Q000473:pathology / Q000503:physiopathology
chemical_list: D005904:Glial Fibrillary Acidic Protein; D034702:RNA-Binding Protein FUS; D010751:Phosphopyruvate Hydratase
keywords: Amyotrophic lateral sclerosis; RNA binding; RNA recognition motif; fused in sarcoma; transgenic animals