PMID- 25173930
OWN - NLM
STAT- MEDLINE
DCOM- 20150225
LR  - 20220330
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 452
IP  - 3
DP  - 2014 Sep 26
TI  - Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs 
      RNA granules formation.
PG  - 600-7
LID - S0006-291X(14)01548-4 [pii]
LID - 10.1016/j.bbrc.2014.08.115 [doi]
AB  - Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders 
      including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes 
      for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly 
      localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and 
      the inclusion of FUS/TLS mutants in the cytoplasm. In the present study, we 
      examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding 
      proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in 
      the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas 
      large aggregates were spontaneously formed in  approximately 10% of those cells. hnRNP A1, 
      hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules 
      under stress conditions, and these were also recruited to FUS mutant-derived 
      spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs 
      and sequestered SMN1 in the detergent insoluble fraction, which also reduced the 
      number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in 
      situ hybridization) assay. In addition, the number of P-bodies was decreased in 
      cells harboring cytoplasmic granules of FUS P525L. These findings raise the 
      possibility that ALS-linked C-terminal FUS mutants could sequester a variety of 
      RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt 
      various aspects of RNA equilibrium and biogenesis.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Takanashi, Keisuke
AU  - Takanashi K
AD  - Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, 
      Japan.
FAU - Yamaguchi, Atsushi
AU  - Yamaguchi A
AD  - Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, 
      Japan. Electronic address: atsyama@restaff.chiba-u.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140828
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Heterogeneous Nuclear Ribonucleoprotein A1)
RN  - 0 (Heterogeneous-Nuclear Ribonucleoprotein Group A-B)
RN  - 0 (Protein Aggregates)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA-Binding Protein FUS)
RN  - 0 (SMN1 protein, human)
RN  - 0 (Survival of Motor Neuron 1 Protein)
RN  - 0 (hnRNP A2)
SB  - IM
MH  - Cell Line
MH  - Cell Nucleus/metabolism/pathology
MH  - Cytoplasm/metabolism/pathology
MH  - Cytoplasmic Granules/*chemistry/metabolism/pathology
MH  - Gene Expression
MH  - HEK293 Cells
MH  - Heterogeneous Nuclear Ribonucleoprotein A1
MH  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B/chemistry/genetics/metabolism
MH  - Humans
MH  - Mutation
MH  - Neurons/*chemistry/metabolism/pathology
MH  - Protein Aggregates
MH  - Protein Aggregation, Pathological/*metabolism
MH  - Protein Structure, Tertiary
MH  - RNA, Messenger/*chemistry/genetics/metabolism
MH  - RNA-Binding Protein FUS/*chemistry/genetics/metabolism
MH  - Survival of Motor Neuron 1 Protein/chemistry/genetics/metabolism
OTO - NOTNLM
OT  - ALS
OT  - FUS/TLS
OT  - SMN1
OT  - hnRNP A/B
EDAT- 2014/09/01 06:00
MHDA- 2015/02/26 06:00
CRDT- 2014/09/01 06:00
PHST- 2014/08/19 00:00 [received]
PHST- 2014/08/22 00:00 [accepted]
PHST- 2014/09/01 06:00 [entrez]
PHST- 2014/09/01 06:00 [pubmed]
PHST- 2015/02/26 06:00 [medline]
AID - S0006-291X(14)01548-4 [pii]
AID - 10.1016/j.bbrc.2014.08.115 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2014 Sep 26;452(3):600-7. doi: 
      10.1016/j.bbrc.2014.08.115. Epub 2014 Aug 28.