PMID- 30150298
OWN - NLM
STAT- MEDLINE
DCOM- 20190617
LR  - 20190617
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 38
IP  - 22
DP  - 2018 Nov 15
TI  - The C9ORF72 Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal 
      Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate 
      Signaling.
LID - 10.1128/MCB.00155-18 [doi]
LID - e00155-18
AB  - A GGGGCC repeat expansion in the C9ORF72 (C9) gene is the most common known cause 
      of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Several 
      mechanisms have been proposed to account for its toxicity, including the 
      possibility that reduced C9 protein levels contribute to disease. To investigate 
      this possibility, we examined the effects of reduced C9 levels in several cell 
      systems. We first showed that C9 knockdown (KD) in U87 glioblastoma cells results 
      in striking morphological changes, including vacuolization and alterations in 
      cell size. Unexpectedly, RNA analysis revealed changes in expression of many 
      genes, including genes involved in endothelin (EDN) signaling and immune system 
      pathways and multiple glutamate cycling genes (e.g., EAAT2), which were verified 
      in several cell models, including astrocytes and brain samples from C9-positive 
      patients. Consistent with deregulation of the glutamate cycling genes, elevated 
      intracellular glutamate was detected in both KD cells and patient astrocytes. 
      Importantly, levels of mRNAs encoding EDN1 and its receptors, known to be 
      elevated in ALS, were sharply increased by C9 KD, likely resulting from an 
      observed activation of NF-kappaB signaling and/or a possible role of a C9 isoform in 
      gene control.
CI  - Copyright (c) 2018 American Society for Microbiology.
FAU - Fomin, Vitalay
AU  - Fomin V
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Richard, Patricia
AU  - Richard P
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Hoque, Mainul
AU  - Hoque M
AD  - Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New 
      Jersey Medical School, Newark, New Jersey, USA.
FAU - Li, Cynthia
AU  - Li C
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Gu, Zhuoying
AU  - Gu Z
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Fissore-O'Leary, Mercedes
AU  - Fissore-O'Leary M
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Tian, Bin
AU  - Tian B
AD  - Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers New 
      Jersey Medical School, Newark, New Jersey, USA.
FAU - Prives, Carol
AU  - Prives C
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA.
FAU - Manley, James L
AU  - Manley JL
AD  - Department of Biological Sciences, Columbia University, New York, New York, USA 
      jlm2@columbia.edu.
LA  - eng
GR  - R01 GM084089/GM/NIGMS NIH HHS/United States
GR  - R35 GM118136/GM/NIGMS NIH HHS/United States
GR  - T32 GM008798/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20181029
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (C9orf72 Protein)
RN  - 0 (C9orf72 protein, human)
RN  - 0 (Endothelins)
RN  - 0 (Glutamates)
RN  - 0 (NF-kappa B)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Amyotrophic Lateral Sclerosis/*genetics
MH  - Astrocytes/physiology
MH  - Brain/physiology
MH  - C9orf72 Protein/*genetics
MH  - Cell Line, Tumor
MH  - Endothelins/*genetics
MH  - Frontotemporal Dementia/*genetics
MH  - Glutamates/*genetics
MH  - Humans
MH  - Immune System/physiology
MH  - Male
MH  - Middle Aged
MH  - NF-kappa B/genetics
MH  - Protein Isoforms/genetics
MH  - RNA, Messenger/genetics
MH  - Signal Transduction/*genetics
PMC - PMC6206455
OTO - NOTNLM
OT  - NF-kappaB signaling
OT  - amyotrophic lateral sclerosis
OT  - endothelin
OT  - glutamate
OT  - glutamine
OT  - transcription
EDAT- 2018/08/29 06:00
MHDA- 2019/06/18 06:00
PMCR- 2019/04/29
CRDT- 2018/08/29 06:00
PHST- 2018/04/02 00:00 [received]
PHST- 2018/08/15 00:00 [accepted]
PHST- 2018/08/29 06:00 [pubmed]
PHST- 2019/06/18 06:00 [medline]
PHST- 2018/08/29 06:00 [entrez]
PHST- 2019/04/29 00:00 [pmc-release]
AID - MCB.00155-18 [pii]
AID - 00155-18 [pii]
AID - 10.1128/MCB.00155-18 [doi]
PST - epublish
SO  - Mol Cell Biol. 2018 Oct 29;38(22):e00155-18. doi: 10.1128/MCB.00155-18. Print 
      2018 Nov 15.