title: FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.
abstract: FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington's disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS+/-double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.
authors.affiliation: CREST(Core Research for Evolutionary Science and Technology), JST, Saitama, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Laboratory for Structural Neuropathology , Brain Science Institute, RIKEN, Saitama, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan.|Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Laboratory for Structural Neuropathology , Brain Science Institute, RIKEN, Saitama, Japan.
authors.forename: Chika
authors.initials: C
authors.lastname: Washizu
authors.affiliation: CREST(Core Research for Evolutionary Science and Technology), JST, Saitama, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Laboratory for Structural Neuropathology , Brain Science Institute, RIKEN, Saitama, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kurosawa
authors.affiliation: Laboratory for Structural Neuropathology , Brain Science Institute, RIKEN, Saitama, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Clinical Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.affiliation: CREST(Core Research for Evolutionary Science and Technology), JST, Saitama, Japan.|Laboratory for Mental Biology, Brain Science Institute, RIKEN, Saitama, Japan.|Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Takumi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Adachi
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Hicks
authors.affiliation: Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Shimogori
authors.affiliation: CREST(Core Research for Evolutionary Science and Technology), JST, Saitama, Japan.|Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.|Laboratory for Structural Neuropathology , Brain Science Institute, RIKEN, Saitama, Japan.|Laboratory for Molecular Mechanisms of Thalamus Development, Brain Science Institute, RIKEN, Saitama, Japan.|Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006720:Homozygote; D000071058:Huntingtin Protein / Q000378:metabolism; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic / Q000378:metabolism; D009154:Mutation / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D034702:RNA-Binding Protein FUS / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C000599551:FUS protein, mouse; D000071058:Huntingtin Protein; D010455:Peptides; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C097188:polyglutamine