title: Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS.
abstract: OBJECTIVE
  The fused in sarcoma/translated in liposarcoma (FUS/TLS) protein was recently identified as a cause of familial amyotrophic lateral sclerosis (ALS), as well as a major component of the inclusion bodies found in subtypes of frontotemporal lobar degeneration (FTLD). These diseases now are collectively known as the novel clinical spectrum, FUS proteinopathy. ALS-linked mutations of FUS are clustered in the C-terminal region; however, the molecular properties of mutant FUS remain unclear. To gain insight into the pathogenesis of FUS proteinopathy, we examined the biochemical and cellular characteristics of mutant FUS in expressing cells.
  
  
  RESULTS
  Expression of ALS-linked FUS mutations resulted in their assembly into cytoplasmic stress granules (SGs), cellular structures that package mRNA and RNA-binding proteins during cell stress. A deletion mutant series revealed that the C-terminal region in FUS is critical for nuclear retention via Ran guanosine triphosphatase-dependent transport machinery. A parallel study of subcellular distribution revealed that ALS-linked mutants additively disturb the function of the C-terminus for nuclear traffic, resulting in cytoplasmic accumulation and the formation of SGs.
  
  
  CONCLUSIONS
  This study demonstrates that mutant FUS, which is missing the nuclear traffic activity of the C-terminus, is dislocated to cytoplasm and assembled into SGs, indicating that disruption of translational regulation and metabolism of mRNA via inappropriate/excessive SGs may be crucial for FUS proteinopathies. Our findings provide new biological and pathological insights into the FUS protein that should help our understanding of the pathogenesis of ALS/FTLD.
authors.affiliation: Department of Neurology, School of Medicine, Keio University, Tokyo, Japan. d-ito@jk9.so-net.ne.jp
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.forename: Morinobu
authors.initials: M
authors.lastname: Seki
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tsunoda
authors.forename: Hidemi
authors.initials: H
authors.lastname: Uchiyama
authors.forename: Norihiro
authors.initials: N
authors.lastname: Suzuki
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics* / Q000502:physiology*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D012333:RNA, Messenger; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins